Farnesyl transferase inhibiting 4-substituted quinoline and quinazoline derivatives

ABSTRACT

This invention comprises the novel compounds of formula (I) 
                         
wherein r, s, t, Y 1 , Y 2 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  have defined meanings, having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of Application No.PCT/EP01/15234, filed Dec. 21, 2001 which application claims priorityfrom EP 00204715.7 filed Dec. 27, 2000.

FIELD OF THE INVENTION

The present invention is concerned with novel 4-substituted quinolineand quinazoline derivatives, the preparation thereof, pharmaceuticalcompositions comprising said novel compounds and the use of thesecompounds as a medicine as well as methods of treatment by administeringsaid compounds.

BACKGROUND OF THE INVENTION

Oncogenes frequently encode protein components of signal transductionpathways which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellular transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes is frequently associated with human cancer. A particular groupof oncogenes is known as ras which have been identified in mammals,birds, insects, mollusks, plants, fungi and yeasts. The family ofmammalian ras oncogenes consists of three major members (“isoforms”):H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highlyrelated proteins generically known as p21^(ras). Once attached to plasmamembranes, the mutant or oncogenic forms of p21^(ras) will provide asignal for the transformation and uncontrolled growth of malignant tumorcells. To acquire this transforming potential, the precursor of thep21^(ras) oncoprotein must undergo an enzymatically catalyzedfarnesylation of the cysteine residue located in a carboxyl-terminaltetrapeptide. Therefore, inhibitors of the enzymes that catalyzes thismodification, i.e. farnesyl transferase, will prevent the membraneattachment of p21^(ras) and block the aberrant growth of ras-transformedtumors. Hence, it is generally accepted in the art that farnesyltransferase inhibitors can be very useful as anticancer agents fortumors in which ras contributes to transformation.

Since mutated oncogenic forms of ras are frequently found in many humancancers, most notably in more than 50% of colon and pancreaticcarcinomas (Kohl et al., Science, vol 260, 1834–1837, 1993), it has beensuggested that farnesyl tranferase inhibitors can be very useful againstthese types of cancer.

In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substitutedquinoline and quinolinone derivatives which suppress the plasmaelimination of retinoic acids. Some of these compounds also have theability to inhibit the formation of androgens from progestines and/orinhibit the action of the aromatase enzyme complex.

In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there aredescribed 2-quinolone derivatives which exhibit farnesyl transferaseinhibiting activity. WO 00/39082 describes a class of novel1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linkedimidazole, which show farnesyl protein transferase and geranylgeranyltransferase inhibiting activity. Other quinolone compounds havingfarnesyl transferase inhibiting activity are described in WO 00/12498,00/12499, 00/47574 and 01/53289.

Unexpectedly, it has been found that the present novel 4-substitutedquinoline and quinazoline compounds show farnesyl protein transferaseinhibiting activity.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns compounds of formula (I):—

or a pharmaceutically acceptable salt or N-oxide or stereochemicallyisomeric form thereof, wherein

-   r and s are each independently 0, 1, 2, 3, 4 or 5;-   t is 0, 1, 2 or 3;-   >Y¹—Y²—is a trivalent radical of formula    >C═N—  (y-1)    >C═CR⁹—  (y-2)    >CH—NR⁹—  (y-3)    >CH—CHR⁹—  (y-4)    -   wherein R⁹ is hydrogen, halo, cyano, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, —(CR²⁰R²¹)_(p)        —C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, halocarbonyl,        hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl or a group of        formula —C₁₋₆alkyl-NR²²R²³, —C₂₋₆alkenyl-NR²²R²³, —CONR²²R²³ or        —NR²²—C₁₋₆alkyl-NR²²R²³;-   Z is —O—, —S—, —SO—, —SO₂—, —NR²²—, -Alk-, C₂₋₄alkenediyl, —O-Alk-,    -Alk-O—, —S(O)₀₋₂-Alk-, -Alk-S(O)₀₋₂, —OC(O)-Alk-, -Alk-OC(O)—,    —NR²²-Alk-, -Alk-NR²²—, —NR²²—C(O)— or —C(O)—NR²²— (in which Alk is    C₁₋₆alkanediyl) and in which the Alk or alkenediyl moiety may be    optionally substituted by one or more substituents independently    selected from C₁₋₆alkyl, C₁₋₆alkyloxy, arylC₁₋₆alkyl or Ar², and    where necessary to establish the configuration of any Z group, the    first atom recited above in any such group being that which is    linked to the Y¹ grouping in formula (I);-   each R¹ and R² is independently azido, hydroxy, halo, cyano, nitro,    C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl,    hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,    hydroxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, R²⁴S C₁₋₆alkyl, trihalomethyl,    arylC₁₋₆alkyl, Het²C₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³,    —C₁₋₆alkylNR²²C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylNR²²-Het²,    —C₁₋₆alkylNR²²—C₁₋₆alkyloxyC₁₋₆alkyl,    —C₁₋₆alkylNR²²—C₁₋₆alkyl-S—C₁₋₆alkyl-Ar²,    —C₁₋₆alkylNR²²—C₁₋₆alkyl-S—C₁₋₆alkyl, —C₁₋₆alkylNR²²C₁₋₆alkyl-Ar²    (in which the C₁₋₆alkyl moiety adjacent to the Ar² is optionally    substituted by C₁₋₆alkyloxycarbonyl), —C₁₋₆alkylNR²²C₁₋₆alkyl-Het²,    —C₁₋₆alkylNR²²COC₁₋₆alkyl, —C₁₋₆alkylNR²²COAlkAr²,    —C₁₋₆alkylNR²²COAr², C₁₋₆alkylsulphonylaminoC₁₋₆alkyl, C₁₋₆alkyloxy,    hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, —OC₁₋₆alkyl-NR²²R²³,    trihalomethoxy, arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, C₁₋₆alkylthio,    C₂₋₆alkenyl, cyanoC₂₋₆alkenyl, —C₂₋₆alkenyl-NR²²R²³,    hydroxycarbonylC₂₋₆alkenyl, C₁₋₆alkyloxycarbonylC₂₋₆alkenyl,    C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkylcarbonyl,    hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³,    —CONR²²—C₁₋₆alkyl-NR²²R²³, —CONR²²—C₁₋₆alkyl-Het²,    —CONR²²—C₁₋₆alkyl-Ar², —CONR²²-Het², —CONR²²Ar²,    —CONR²²—O—C₁₋₆alkyl, —CONR²²—C₁₋₆alkenyl, —NR²²R²³, —OC(O)R²⁴,    —CR²⁴═NR²⁵, —CR²⁴═N—OR²⁵, —NR²⁴C(O) NR²²R²³, —NR²⁴SO₂R²⁵,    —NR²⁴C(O)R²⁵, —S(O)₀₋₂R²⁴, —SO₂NR²⁴R²⁵, —C(NR²⁶R²⁷)═NR²⁸; —Sn(R²⁴)₃,    —SiR²⁴R²⁴R²⁵, —B(OR²⁴)₂, —P(O)OR²⁴OR²⁵, Ar²oxy, Het²-oxy,    -   or a group of formula        -Z, —CO-Z or —CO—NR^(y)-Z        -   in which R^(y) is hydrogen or C₁₋₄alkyl and Z is phenyl or a            5- or 6-membered heterocyclic ring containing one or more            heteroatoms selected from oxygen, sulphur and nitrogen, the            phenyl or heterocyclic ring being optionally substituted by            one or two substituents each independently selected from            halo, cyano, —COOR²⁴, aminocarbonyl, C₁₋₆alkylthio, hydroxy,            —NR²²R²³, C₁₋₆alkylsulphonylamino, C₁₋₆alkyl, haloC₁₋₆alkyl,            C₁₋₆alkyloxy or phenyl; or-   two R¹ or R² substituents adjacent to one another on the phenyl ring    may form together a bivalent radical of formula    —O—CH₂—O—  (a-1)    —O—CH₂—CH₂—O—  (a-2)    —O—CH═CH—  (a-3)    —O—CH₂—CH₂—  (a-4)    —O—CH₂—CH₂—CH₂—  (a-5)    —CH═CH—CH═CH—  (a-6)    -   p is 0 to 5;    -   R²⁰ and R²¹ are independently hydrogen or C₁₋₆ alkyl and are        independently defined for each iteration of p in excess of 1;    -   R²² and R²³ are independently hydrogen, C₁₋₆ alkyl or        —(CR²⁰R²¹)_(p) —C₃₋₁₀cycloalkyl, or together with the adjacent        nitrogen atom form a 5- or 6-membered heterocyclic ring        optionally containing one, two or three further heteroatoms        selected from oxygen, nitrogen or sulphur and optionally        substituted by one or two substituents each independently        selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        haloC₁₋₆alkyl, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,        C₁₋₆alkyloxycarbonyl, aminocarbonyl, mono- or        di-(C₁₋₆alkyl)aminocarbonyl, amino, mono- or        di-(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonylamino, oxime, or phenyl;    -   R²⁴ and R²⁵ are independently hydrogen, C₁₋₆ alkyl,        —CR₂₀R₂₁)p—C₃₋₁₀cycloalkyl or arylC₁₋₆alkyl;    -   R²⁶, R²⁷ and R²⁸ are independently hydrogen and C₁₋₆alkyl or        C(O) C₁₋₆alkyl;-   R³ is hydrogen, halo, cyano, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)    —C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyloxyC₁₋₆alkyl,    C₁₋₆alkylthioC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,    C₁₋₆alkylcarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,    —C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkyl-CONR²²R²³, arylC₁₋₆alkyl,    Het²C₁₋₆alkyl, C₂₋₆alkenyl, —C₂₋₆alkenyl NR²²R²³, C₂₋₆alkynyl,    hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl, or Het²; or    -   a radical of formula        —O—R¹⁰  (b-1)        —S—R¹⁰  (b-2)        —NR¹¹R¹²  (b-3)        —N═CR¹⁰R¹¹  (b-4)        -   wherein R¹⁰ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)            —C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,            C₁₋₆alkylcarbonyl, aryl, a group of formula —NR²²R²³ or            —C₁₋₆alkylC(O)OC₁₋₆alkyl NR²²R²³, or a radical of formula            -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;        -   R¹¹ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,            C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl;        -   R¹² is hydrogen, hydroxy, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)            —C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl,            C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆alkyloxy, a group of            formula —NR²²R²³, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl,            haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl,            Het²C₁₋₆alkylcarbonyl, arylcarbonyl, C₁₋₆alkyloxycarbonyl,            trihaloC₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl,            aminocarbonyl, mono- or di-(C₁₋₆alkyl)aminocarbonyl wherein            the alkyl moiety may optionally be substituted by one or            more substituents independently selected from aryl and            C₁₋₆alkyloxycarbonyl substituents; aminocarbonylcarbonyl,            mono- or di-(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical            of formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;        -   R¹³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,            C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl,            hydroxyC₁₋₆alkyl, aryl or arylC₁₋₆alkyl;        -   R¹⁴ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p) —C₃₋₁₀cycloalkyl,            C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl;        -   R¹⁵ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,            C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, aryl or            arylC₁₋₆alkyl;-   R⁴ is a radical of formula

-   -   wherein R¹⁶ is hydrogen, halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)        —C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,        C₁₋₆alkylS(O)₀₋₂C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, a group        of formula —NR²²R²³, —NHCOC₁₋₆alkyl, hydroxycarbonyl,        C₁₋₆alkyloxycarbonyl or aryl,    -   R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p) —C₃₋₁₀cycloalkyl,        hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aryl C₁₋₆alkyl,        trifluoromethyl, trifluoromethylC₁₋₆alkyl,        hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, mono-        or di-(C₁₋₆alkyl)aminosulphonyl or —C₁₋₆alkyl P(O)OR²⁴OR²⁵;    -   R¹⁸ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p) —C₃₋₁₀cycloalkyl,        arylC₁₋₆alkyl or C₁₋₆alkyloxyC₁₋₆alkyl;    -   R^(18a) is hydrogen, —SH or —SC₁₋₄alkyl;

-   R⁵ is cyano, hydroxy, halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)    —C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy,    arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl, or a group of formula —NR²²R²³ or —CONR²²R²³;

-   R⁶ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p) —C₃₋₁₀cycloalkyl,    cyanoC₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, aminocarbonylC₁₋₆alkyl or    —C₁₋₆alkyl-NR²²R²³, R²⁴SO₂, R²⁴SO₂C₁₋₆alkyl, —C₁₋₆alkyl-OR²⁴,    —C₁₋₆alkyl-SR²⁴, —C₁₋₆alkylCONR²²—C₁₋₆alkyl-NR²²R²³,    —C₁₋₆alkylCONR²²—C₁₋₆alkyl-Het², —C₁₋₆alkyl CONR²²—C₁₋₆alkyl-Ar²,    —C₁₋₆alkyl CONR²²-Het², —C₁₋₆alkyl CONR²²Ar², —C₁₋₆alkyl    CONR²²—O—C₁₋₆alkyl, —C₁₋₆alkyl CONR²²—C₁₋₆alkenyl, -Alk-Ar² or    -Alk-Het²;

-   R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form a trivalent    radical of formula:—

—CR³⁰═CR³¹—N═ (x-1) —CR³⁰═CR³¹—CR³²═ (x-6) —CR³⁰═N—N═ (x-2)—CR³⁰═N—CR³¹═ (x-7) —C(═O)—NH—N═ (x-3) —C(═O)—NH—CR³⁰═ (x-8) —N═N—N═(x-4) —N═N—CR³⁰═ (x-9) or —N═CR³⁰—N═ (x-5) —CH₂—(CH₂)_(0–1)—CH₂—N═(x-10)

-   -   wherein each R³⁰, R³¹ and R³² are independently hydrogen, C₁₋₆        alkyl, —OR²⁴, —COOR²⁴, —NR²²R²³, —C₁₋₆ alkylOR²⁴, —C₁₋₆        alkylSR²⁴, R²³R²²NC₁₋₆alkyl-, —CONR²²R²³, C₂₋₆alkenyl,        C₂₋₆alkenylAr², C₂₋₆alkenylHet², cyano, amino, thio, C₁₋₆        alkylthio, —O-Ar², —S-Ar² or Ar²;    -   Ar² is phenyl, naphthyl or phenyl or naphthyl substituted by one        to five substituents each independently selected from halo,        hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³,        C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        aryloxy, —NR²²R²³, C₁₋₆alkylsulfonylamino, oxime or phenyl, or a        bivalent substituent of formula —O—CH₂—O— or —O—CH₂—CH₂—O—;    -   Het² is a mono- or bi-cyclic heterocyclic ring containing one or        more heteroatoms selected from oxygen, sulphur and nitrogen and        optionally substituted by one or two substituents each        independently selected from halo, hydroxy, cyano, nitro,        C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃,        hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³,        C₁₋₆alkylsulfonylamino, oxime or phenyl.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₄alkyl defines straight and branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl,2-methylpropyl and the like; C₁₋₆alkyl includes C₁₋₄alkyl and the higherhomologues thereof having 5 to 6 carbon atoms such as, for example,pentyl, 2-methyl-butyl, hexyl, 2-methylpentyl and the like;C₁₋₆alkanediyl defines bivalent straight and branched chained saturatedhydrocarbon radicals having from 1 to 6 carbon atoms, such as, forexample, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof;haloC₁₋₆alkyl defines C₁₋₆alkyl containing one or more halo substituentsfor example trifluoromethyl; C₂₋₆alkenyl defines straight and branchedchain hydrocarbon radicals containing one double bond and having from 2to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl,2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like. The term“S(O)” refers to a sulfoxide and “S(O)₂” to a sulfone. Aryl definesphenyl, naphthalenyl or phenyl substituted with one or more substituentseach independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl, cyano, hydroxycarbonyl.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The compounds of formula (I) which have basic properties can beconverted in their pharmaceutically acceptable acid addition salts bytreating said base form with an appropriate acid. Appropriate acidscomprise, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.butanedioic acid), maleic, fuimaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

The term acid addition salts also comprises the hydrates and the solventaddition forms which the compounds of formula (I) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The term stereochemically isomeric forms of compounds of formula (I), asused hereinbefore, defines all possible compounds made up of the sameatoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereomers and/orenantiomers of the basic molecular structure of said compound. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the pharmaceutically acceptable acid addition salts andall stereoisomeric forms.

Examples of compounds of formula (I) include those wherein one or moreof the following restrictions apply:

-   -   r and s are each independently 0, 1 or 2;    -   t is 0 or 1;    -   >Y¹—Y²—is a trivalent radical of formula        >C═N—  (y-1)        >C═CR⁹—  (y-2)        -   wherein R⁹ is hydrogen, cyano, halo, C₁₋₆alkyl,            hydroxyC₁₋₆alkyl, hydroxycarbonyl or aminocarbonyl;    -   Z is C₁₋₂ alkanediyl;    -   R¹ is halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,        trihalomethyl, trihalomethoxy, C₂₋₆alkenyl,        hydroxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy,        hydroxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, C₁₋₆alkylthio,        hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³ or —CH═NOR²⁵;        or two R¹ substituents adjacent to one another on the phenyl        ring may independently form together a bivalent radical of        formula        —O—CH₂—O—  (a-1)        —O—CH₂—CH₂—O—  (a-2)    -   R² is halo, cyano, nitro, C₁₋₆alkyl, cyanoC₁₋₆alkyl, —C₁₋₆alkyl        NR²²R²³; cyanoC₂₋₆alkenyl, —NR²²R²³, —CHO, —CR²⁴═N—OR²⁵,        C₁₋₆alkyloxycarbonyl, —CO NR²²R²³; or        -   two R² substituents adjacent to one another on the phenyl            ring may independently form together a bivalent radical of            formula            —O—CH₂—O—  (a-1)            —O—CH₂—CH₂—O—  (a-2)    -   R³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p) —C₃₋₁₀cycloalkyl,        haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, —C₁₋₆alkyl NR²²R²³, Het²C₁₋₆alkyl,        —C₂₋₆alkenyl NR²²R²³, or -Het²; or a group of formula        —O—R¹⁰  (b-1)        —NR¹¹R¹²  (b-3)        -   wherein R¹⁰ is hydrogen, C₁₋₆alkyl, or            —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or a group of formula            -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;        -   R¹¹ is hydrogen or C₁₋₆alkyl;        -   R¹² is hydrogen, hydroxy, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)            —C₃₋₁₀cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl,            arylC₁₋₆alkylcarbonyl, Het²C₁₋₆alkylcarbonyl, aminocarbonyl,            or a radical of formula -Alk-OR¹³ or Alk-NR¹⁴R¹⁵;            -   wherein Alk is C₁₋₆alkanediyl;        -   R¹³ is hydrogen, C₁₋₆alkyl or            —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;        -   R¹⁴ is hydrogen, C₁₋₆alkyl, or            —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;        -   R¹⁵ is hydrogen or C₁₋₆alkyl;    -   R⁴ is a radical of formula (c-2) or (c-3)        -   wherein R¹⁶ is hydrogen, halo or C₁₋₆alkyl,            -   R¹⁷ is hydrogen, C₁₋₆alkyl,                —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkyloxyC₁₋₆alkyl or                trifluoromethyl;            -   R¹⁸ is hydrogen, C₁₋₆alkyl or                —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;            -   R^(18a) is hydrogen:    -   R⁵ is cyano, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyloxy or        C₁₋₆alkyloxycarbonyl:    -   R⁶ is hydrogen, C₁₋₆alkyl, —C₁₋₆alcylCO₂R²⁴, —C₁₋₆alkylC(O)NR²²        R²³, -Alk-Ar², -AlkHet² or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,    -   R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form a trivalent        radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9)    -   Het² is a 5- or 6-membered monocyclic heterocyclic ring        containing one, two or three heteroatoms selected from oxygen,        sulphur or nitrogen for example pyrrolidinyl, imidazolyl,        triazolyl, pyridyl, pyrimidinyl, furyl, morpholinyl,        piperazinyl, piperidinyl, thiophenyl, thiazolyl or oxazolyl, or        a 9- or 10-membered bicyclic heterocyclic ring especially one in        which a benzene ring is fused to a heterocyclic ring containing        one, two or three heteroatoms selected from oxygen, sulphur or        nitrogen for example indolyl, quinolinyl, benzimidazolyl,        benzotriazolyl, benzoxazolyl, benzothiazolyl or benzodioxolanyl.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   -   r is 0, 1 or 2;    -   s is 0 or 1;    -   t is 0;    -   >Y¹—Y²—is a trivalent radical of formula (y-1) or (y-2), wherein        R⁹ is hydrogen or halo;    -   Z is C₁₋₂ alkanediyl;    -   R¹ is halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or two R¹        substituents ortho to one another on the phenyl ring may        independently form together a bivalent radical of formula (a-1);    -   R² is halo, cyano, nitro, CHO, —CR²⁴═N—OR²⁵ in which R²⁴ is        hydrogen and R²⁵ is hydrogen or C₁₋₆alkyl, or two R²        substituents ortho to one another on the phenyl ring may        independently form together a bivalent radical of formula (a-1);    -   R³ is hydrogen or a group of formula (b-1) or (b-3) wherein        -   R¹⁰ is hydrogen or a group of formula -Alk-OR¹³.        -   R¹¹ is hydrogen;        -   R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy or            C₁₋₆alkyloxy;        -   Alk is C₁₋₆alkanediyl and R¹³ is hydrogen;    -   R⁴ is a group of formula (c-2) or (c-3) wherein        -   R¹⁶ is hydrogen, halo or C₁₋₆alkyl;        -   R¹⁷ is hydrogen or C₁₋₆alkyl;        -   R¹⁸ is hydrogen or C₁₋₆alkyl;        -   R^(18a) is hydrogen;    -   R⁶ is hydrogen, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,        —C₁₋₆alkylCO₂R²⁴, —C₁₋₆alkylC(O)NR²²R²³, -Alk-Ar² or -AlkHet² or        C₁₋₆alkyl;    -   R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form a trivalent        radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9)    -   aryl is phenyl.

A particular group of compounds consists of those compounds of formula(I) wherein r is 0 or 1, s is 1, t is 0, >Y¹—Y² is a trivalent radicalof formula (y-1) or (y-2), Z is C₁₋₂ alkanediyl R¹ is halo, C₁₋₆alkyl orforms a bivalent radical of formula (a-1), R² is halo or cyano, R³ ishydrogen or a radical of formula (b-1) or (b-3) wherein R¹⁰ is hydrogenor -Alk-OR¹³, R¹¹ is hydrogen, R¹² is hydrogen or C₁₋₆alkylcarbonyl andR¹³ is hydrogen; R⁴ is a radical of formula (c-2) or (c-3) wherein R¹⁶is hydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl and R^(18a) is hydrogen;

-   R⁶ is hydrogen, C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴    (R²⁴═H,Et), aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet²;-   R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form a trivalent    radical of formula (x-2), (x-3) or (x-4).

More preferred compounds are those compounds of formula (I) wherein r is0 or 1, s is 1, t is 0, >Y¹—Y² is a trivalent radical of formula (y-1)or (y-2), Z is C₁₋₂ alkanediyl, R¹ is halo, preferably chloro and mostpreferably 3-chloro, R² is halo, preferably 4-chloro or 4-fluoro, orcyano, preferably 4-cyano, R³ is hydrogen or a radical of formula (b-1)or (b-3), R⁹ is hydrogen, R¹⁰ is hydrogen, R¹¹ is hydrogen and R¹² ishydrogen or C₁₋₆alkylcarbonyl, R⁴ is a radical of formula (c-2) or (c-3)wherein R¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl and R^(18a)is hydrogen;

-   R⁶ is hydrogen, C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or —C₁₋₆alkylAr²;-   R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form a trivalent    radical of formula (x-2) or (x-4).

Especially preferred compounds are those compounds of formula (I)wherein r and s are 1, t is 0, >Y¹—Y² is a trivalent radical of formula(y-1) or (y-2), Z is —(CH₂)₂—, R¹ is halo, preferably chloro, and mostpreferably 3-chloro, R² is halo, preferably chloro, and most preferably4-chloro, or cyano, preferably 4-cyano, R³ is a radical of formula (b-1)or (b-3) wherein R⁹ is hydrogen, R¹⁰ and R¹¹ are hydrogen and R¹² ishydrogen or C₁₋₆alkylcarbonyl; R⁴ is a radical of formula (c-2) or (c-3)wherein R¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl preferably methyl, R¹⁸ isC₁₋₆alkyl preferably methyl and R^(18a) is hydrogen; R⁶ is hydrogen,C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or —C₁₋₆alkylAr²; R⁷ is oxygen orsulphur; or R⁶ and R⁷ together form a trivalent radical of formula(x-4).

The most preferred compounds according to the invention are:—

-   6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone-   4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone-   α-(4-chlorophenyl)-5-[2-(3-chlorophenyl)ethyl]-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinoline-7-methanamine-   N-[(4-chlorophenyl)[5-[2-(3-chlorophenyl)ethyl]tetrazolo[1,5-α]quinolin-7-yl](1-methyl-1H-imidazol-5-yl)methyl]-acetamide-   N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)[5-(2-phenylethyl)tetrazolo[1,5-α]quinolin-7-yl]methyl]-acetamide    and-   4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone-   and their pharmaceutically acceptable salts.

The compounds of formula (I) and their pharmaceutically acceptable saltsand N-oxides and stereochemically isomeric forms thereof may be preparedin conventional manner, for example by a process which comprises:—

-   a) cyclising a compound of formula (II):

with a reagent serving to form a compound of formula (I) in which R⁶ ishydrogen and R⁷ is oxygen;

-   b) reacting a compound of formula (III):

in which W¹ represents a replaceable or reactive group, with a reagentserving either to react with or replace the W¹ group in compound (III)to form a compound of formula (I) in which R⁶ is hydrogen and R⁷ is anoxygen or sulphur group or to react with the W¹ group and the adjacentnitrogen atom to form directly or indirectly a compound of formula (I)in which R⁶ and R⁷ together form a trivalent radical selected fromformulae (x-1) to (x-10); or

-   c) reacting a compound of formula (IV):

in which W² is a replaceable group, with an imidazole reagent serving toreplace the group W² with an R⁴ group of formula (c-1); or

-   d) reacting a compound of formula (V):

with an imidazole reagent to form a compound of formula (I) in which R⁴is a group of formula (c-2), or with a3-mercapto-4-C₁₋₆alkyl-1,2,4-triazole reagent to form the corresponding3-mercapto-4-C₁₋₆alkyl-1,2,4-triazole derivative, which is optionallymethylated to form the corresponding 3-methylmercapto derivative, andsubsequently removing the 3-mercapto or 3-methylmercapto group to form acompound of formula (I) in which R⁴ is a group of formula (c-3) in whichR¹⁸ is a C₁₋₆alkyl group;or with a 3-bromopyridyl reagent to form a compound of formula (I)wherein R⁴ is a group of formula (c-4); or

-   e) reacting a compound of formula (VI):

with a reagent serving to convert the said compound (VI) to a compoundof formula (I) in which R⁶ is hydrogen and R⁷ is oxygen;and optionally effecting one or more of the following conversions in anydesired order:—

-   -   (i) converting a compound of formula (I) into a different        compound of formula (I);    -   (ii) converting a compound of formula (I) in to a        pharmaceutically acceptable salt or N-oxide thereof;    -   (iii) converting a pharmaceutically acceptable salt or N-oxide        of a compound of formula (I) into the parent compound of formula        (I);    -   (iv) preparing a stereochemical isomeric form of a compound of        formula (I) or a pharmaceutically acceptable salt or N-oxide        thereof.

With regard to process a), this can be effected as described for examplein WO 97/21701 and WO98/49157 referred to above. Thus, the cyclisationmay be effected for example by subjecting the compound of formula (II)to an acetylation reaction, e.g. by treatment with the anhydride of acarboxylic acid, e.g. acetic anhydride in a reaction-inert solvent, e.g.toluene, and subsequent reaction with a base such as potassiumtert-butoxide in a reaction-inert solvent such as 1,2-dimethoxyethane.

With regard to process b), this can also be effected as described forexample in WO 97/21701 and WO98/49157 referred to above for thepreparation of compounds in which R⁷ is oxygen, for example byhydrolysis of an ether of formula (II) in which W1 is C₁₋₆alkyloxy in anaqueous acid solution such hydrochloric acid

With regard to process b), for the preparation of compounds in which R⁶and R⁷ together form a trivalent radical of formula (x-1) to (x-10),this can be effected as described for example in WO 00/39082 referred toabove. For example, when W¹ is chloro, the compound of formula (III) canbe reacted with an azide compound for example sodium azide to form acorresponding compound of formula (I) in which R⁶ and R⁷ together form atrivalent radical of formula (x-4).

With regard to process c), this can be effected for example byN-alkylating an intermediate of formula (IV), wherein W² is anappropriate leaving group such as, for example, chloro, bromo,methanesulfonyloxy or benzenesulfonyloxy, with an intermediate offormula (IVa) to form a a compound of formula (I) in which R⁴ is a groupof formula (c-1) represented by compounds of formula (I-a):

The reaction can be performed in a reaction-inert solvent such as, forexample, acetonitrile, and optionally in the presence of a suitable basesuch as, for example, sodium carbonate, potassium carbonate ortriethylamine. Stirring may enhance the rate of the reaction. Thereaction may conveniently be carried out at a temperature rangingbetween room temperature and reflux temperature.

Also, compounds of formula (I-a) can be prepared by reacting anintermediate of formula (V) in which W² is hydroxy with an intermediateof formula (X), wherein Y is oxygen or sulfur, such as, for example, a1,1′-carbonyldiimidazole.

Said reaction may conveniently be conducted in a reaction-inert solvent,such as, e.g. tetrahydrofuran, optionally in the presence of a base,such as sodium hydride, and at a temperature ranging between roomtemperature and the reflux temperature of the reaction mixture.

With regard to process d), the compounds of formula (I) wherein R⁴represents a radical of formula (c-2), R³ is hydroxy and R¹⁷ isC₁₋₆alkyl, said compounds being referred to as compounds of formula(I-b-1) may be prepared by reacting an intermediate ketone of formula(V) with an intermediate of formula (III-1). Said reaction requires thepresence of a suitable strong base, such as, for example, butyl lithiumin an appropriate solvent, such as, for example, tetrahydrofuran, andthe presence of an appropriate silane derivative, such as, for example,triethylchlorosilane. During the work-up procedure an intermediatesilane derivative is hydrolyzed. Other procedures with protective groupsanalogous to silane derivatives can also be applied.

Also, the compounds of formula (I), wherein R⁴ is a radical of formula(c-2), R³ is hydroxy and R¹⁷ is hydrogen, said compounds being referredto as compounds of formula (I-b-2) may be prepared by reacting anintermediate ketone of formula (V) with a intermediate of formula(III-2), wherein PG is a protective group such as, for example, asulfonyl group, e.g. a dimethylaminosulfonyl group, which can be removedafter the addition reaction. Said reaction is conducted analogously asfor the preparation of compounds of formula (I-b-1), followed by removalof the protecting group PG, yielding compounds of formula (I-b-2).

Also with regard to process c), the compounds of formula (I) wherein R⁴represents a radical of formula (c-3) may be prepared by reacting thecompound of formula (IV) with the triazole reagent, preferably in areaction-inert solvent such as tetrahydrofuran, in the presence of astrong base such as butyl lithium at a temperature ranging from −78° C.to room temperature. When the 3-mercapto derivative is methylated, thisis conveniently effected with methyl iodide in the presence of a basesuch as sodium methylate. Removal of the 3-mercapto group isconveniently effected with sodium nitrite, for example in THF/H₂O in thepresence of nitric acid. Removal of the 3-methylmercapto group isconveniently effected with Raney Nickel in ethanol or acetone.

With regard to process e), this may be effected for example as describedin WO 97/21701 referred to above, by reacting the nitrone of formula(VI) with the anhydride of a carboxylic acid, e.g. acetic anhydride,thus forming the corresponding ester on the 2-position of the quinolinemoiety, which ester can then be hydrolysed in situ to the correspondingquinolinone using a base such potassium carbonate. Alternatively theabove nitrone can be reacted with tosyl chloride to prepare thecorresponding tosylate which can then be hydrolysed in situ.

Examples of the interconversion of one compound of formula (I) into adifferent compound of formula (I) include the following reactions:—

-   a) compounds of formula (I-b) can be converted to compounds of    formula (I-c), defined as a compound of formula (I) wherein R⁴ is a    radical of formula (c-2) and R³ is hydrogen, by submitting the    compounds of formula (I-b) to appropriate reducing conditions, such    as, e.g. stirring in acetic acid in the presence of formamide, or    treatment with sodium borohydride/trifluoroacetic acid.

-   b) compounds of formula (I-b) can be converted to compounds of    formula (I-f) wherein R³ is halo, by reacting the compounds of    formula (I-b) with a suitable halogenating agent, such as, e.g.    thionyl chloride or phosphorus tribromide. Successively, the    compounds of formula (I-f) can be treated with a reagent of formula    H—NR¹¹R¹² in a reaction-inert solvent, thereby yielding compounds of    formula (I-g).

-   c) compounds of formula (I-b) can be converted into compounds of    formula (I-g) for example by treatment with SOCl₂, and then    NH₃/iPrOH, e.g. in a tetrahydrofuran solvent, or by treatment with    acetic acid ammonium salt at a temperature ranging from 120 to 180°    C., or by treatment with sulfamide at a temperature ranging from 120    to 180° C.;-   d) compounds of formula (I-f) can be converted into compounds of    formula (I-c) for example by treatment with SnCl₂ in the presence of    concentrated HCl in acetic acid at reflux;-   e) compounds of formula (I) in which X is oxygen can be converted    into corresponding compounds of formula (I) in which X is sulphur    with a reagent such as phosphorus pentasulfide or Lawesson's reagent    in a suitable solvent such as, for example, pyridine;-   f) compounds of formula (I) in which R⁹ is C₁₋₆alkyloxycarbonyl can    be converted into corresponding compounds of formula (I) in which R⁹    is hydroxymethyl by conventional reduction procedures for example    with the use of lithium aluminium hydride;-   g) compounds of formula (I) in which R³ is a radical of formula    (b-1) in which R¹⁰ is hydrogen can be converted into corresponding    compounds of formula (I) in which R³ is a radical of formula (b-3)    in which R¹¹ hydrogen and R¹² is C₁₋₆alkylcarbonyl for example by    with an appropriate nitrile for example acetonitrile;-   h) compounds of formula (I) in which R⁶ is hydrogen can be converted    into corresponding compounds of formula (I) in which R⁶ is C₁₋₆alkyl    for example by treatment with an appropriate alkylating agent, e.g.    a C₁₋₆ alkyl halide in the presence of a base for example NaH in an    appropriate solvent such as THF or DMF.

The compounds of formula (I) may also be converted into each other viaart-known reactions or functional group transformations. A number ofsuch transformations are already described hereinabove. Other examplesare hydrolysis of carboxylic esters to the corresponding carboxylic acidor alcohol; hydrolysis of amides to the corresponding carboxylic acidsor amines; hydrolysis of nitrites to the corresponding amides; aminogroups on imidazole or phenyl may be replaced by a hydrogen by art-knowndiazotation reactions and subsequent replacement of the diazo-group byhydrogen; alcohols may be converted into esters and ethers; primaryamines may be converted into secondary or tertiary amines; double bondsmay be hydrogenated to the corresponding single bond.

The intermediates and starting materials used in the above-describedprocesses my be prepared in conventional manner using procedures knownin the art for example as described in the above-mentioned patentspecifications WO 97/16443, WO 97/21701, WO 98/40383, WO 98/49157 and WO00/39082.

Thus compounds of formula (III) in which W¹ is chloro, used as startingmaterials in process b), can be prepared, for example in the case whereR³ is hydroxy and R⁴ is a radical of formula (c-2) or (c-3), by reactinga compound of formula (VII):

with an imidazole, a triazole or a pyridyl reagent in an analogousmanner to that described above for process d).

The compound of formula (VII) can be prepared by chlorinating a compoundof formula (VIII):

The chlorination of the above compound of formula (VII) can beconveniently effected by treatment with phosphorus oxychloride.

The compound of formula (VIII) can be prepared by oxidising a compoundof formula (IX):

The oxidation of the compound of formula (IX) can be effected forexample by treatment of

the compound with a per-acid such as 3-chloro-benzenecarboperoxoic acidpreferably in a reaction-inert solvent such as dichloromethane.

The compound of formula (IX) can be prepared for example from a compoundof formula (X):

in which W³ is an oxo group or a protected oxo group such as anethylenedioxy group and W⁴ is a leaving group or a precursor group forthe moiety (A):

When W⁴ is a leaving group, this can be for example a halo e.g. chlorogroup which can be reacted with a compound of formula:

in which W⁵ is a suitable leaving group: for example when Z is —O—, theleaving group W⁵ can be hydrogen, and when W⁴ is chloro, the reactioncan be conducted in the presence of sodium hydride preferably in asolvent such as dimethylformamide.

When W⁴ is a precursor group, this can be for example a methyl group,which can be reacted with a compound of formula

in which W⁶ is a suitable leaving group such as a halo (e.g. chloro)group to form a compound of formula (I) in which Z is a —CH₂CH₂— group;the reaction is advantageously effected in a basic medium for examplecomprising N-(1-methylethyl)-2-propanamine andN,N,N′,N′-tetramethyl-1,2-ethanediamine with butyl lithium in a solventsuch as tetrahydrofuran.

The oxo protection can be removed following the reaction of the compoundof formula (X) for example by treatment with an acid such ashydrochloric acid in a solvent such as methanol. Alternatively, the oxoprotection can be retained to form corresponding oxo-protected forms ofthe compounds of formulae (VII) or (VIII), such protection being removedafter the respective formation of such compounds; the removal may beeffected in an analogous manner to that described for the conversion ofcompounds of formula (X) to compounds of formula (IX).

The compounds of formula (X) used as an intermediates above can beprepared in conventional manner. Thus, when W⁴ is a methyl group, thecompound can be prepared by reacting a compound of formula (XI):

with an acid such as hydrochloric acid, then with FeCl₃ and ZnCl₂ beforethe addition of 3-buten-2-one. Compounds of formula (X) in which W⁴ is adifferent C₁₋₆alkyl group can be obtained in analogous manner.

Compounds of formula (X) in which W⁴ is a chloro group can be obtainedby chlorination of the corresponding hydroxy group in a compound offormula (XII):

Compounds of formula (XII) can be prepared by cyclisation of compoundsof formula (XI) in conventional manner.

Compounds of formula (III) in which W¹ is a C₁₋₆alkyloxy group and R³ ishydroxy can alternatively be prepared for example by reacting a compoundof formula (XIII):

in which W⁷ is a leaving group for example a halo, e.g. bromo group,with a compound of formula (XIV):

The reaction of the compounds of formulae (XIII) and (XIV) can beconveniently effected in the presence of n-butyl lithium, e.g. insolvent such as tetrahydrofuran.

The above compound of formula (XIII) can be prepared from acorresponding quinolinone compound for example by treatment with POCl₃to form the corresponding 2-chloro compound which can then be reactedwith an appropriate C₁₋₆alkanol to form the desired 2-C₁₋₆alkoxycompound. The starting quinolinone compound can be obtained by acyclisation reaction as described in the Examples below.

The compounds of formula (IV) used as starting materials in process c)above for example in which R³ is hydrogen and W² is hydroxy can beprepared by reduction of corresponding compounds of formula (V), used asstarting materials for process d); the reduction is convenientlyeffected by sodium borohydride in a solvent such as methanol. Thecorresponding compounds of formula (IV) in which W² is halo for examplechloro can be obtained by halogenating the former hydroxy compounds,e.g. with thionyl chloride.

The compounds of formula (V) used as starting materials in process d)can be prepared for example by treatment of a compound of formula (VIII)above in an analogous manner to that described for process e), byreaction with tosyl chloride and subsequent hydrolysis of the resultingtosylate. If desired the resulting compound in which R⁶ is hydrogen canbe converted to a compound with a different R⁶ group as described above.

Alternatively, compounds of formula (V) can be obtained by cyclisationof a compound of formula (XV):

and if necessary removing the W³ oxo protection.

The cyclisation of the compound of formula (XV) can be effected inconventional manner for example using procedures analogous to thosedescribed in WO 97/16443, advantageously by subjecting the compound offormula (XV) to an acetylation reaction, e.g. by treatment with aceticanhydride in a reaction-inert solvent, e.g. toluene, optionally in thepresence of a base to capture acid liberated during the reaction, andsubsequent treatment with a base such potassium tert-butoxide in areaction-inert solvent, e.g. 1,2-dimethoxyethane. The W³ oxo protectedgroup can be converted to the free oxo group in conventional manner, forexample as described above.

The compounds of formula (I) and some of the intermediates have at leastone stereogenic center in their structure. This stereogenic center maybe present in a R or a S configuration.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereoisomeric forms thereof have valuablepharmacological properties in that they have a potent farnesyl proteintransferase (FPTase) inhibitory effect.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of the invention. Abnormal growth of cells refers to cellgrowth independent of normal regulatory mechanisms (e.g. loss of contactinhibition). This includes the abnormal growth of: (1) tumor cells(tumors) expressing an activated ras oncogene; (2) tumor cells in whichthe ras protein is activated as a result of oncogenic mutation ofanother gene; (3) benign and malignant cells of other proliferativediseases in which aberrant ras activation occurs. Furthermore, it hasbeen suggested in literature that ras oncogenes not only contribute tothe growth of tumors in vivo by a direct effect on tumor cell growth butalso indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak.J. et al, Cancer Research, 55, 4575–4580, 1995). Hence,pharmacologically targeting mutant ras oncogenes could conceivablysuppress solid tumor growth in vivo, in part, by inhibitingtumor-induced angiogenesis.

This invention also provides a method for inhibiting tumor growth byadministering an effective amount of a compound of the presentinvention, to a subject, e.g. a mammal (and more particularly a human)in need of such treatment. In particular, this invention provides amethod for inhibiting the growth of tumors expressing an activated rasoncogene by the administration of an effective amount of the compoundsof the present invention. Examples of tumors which may be inhibited, butare not limited to, lung cancer (e.g. adenocarcinoma and includingnon-small cell lung cancer), pancreatic cancers (e.g. pancreaticcarcinoma such as, for example exocrine pancreatic carcinoma), coloncancers (e.g. colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), prostate cancer including theadvanced disease, hematopoietic tumors of lymphoid lineage (e.g. acutelymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloidleukemias (for example, acute myelogenous leukemia (AML)), thyroidfollicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymalorigin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas,teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin(e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer),kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermalcarcinoma.

This invention may also provide a method for inhibiting proliferativediseases, both benign and malignant, wherein ras proteins are aberrantlyactivated as a result of oncogenic mutation in genes. With saidinhibition being accomplished by the administration of an effectiveamount of the compounds described herein, to a subject in need of such atreatment. For example, the benign proliferative disorderneuro-fibromatosis, or tumors in which ras is activated due to mutationor overexpression of tyrosine kinase oncogenes, may be inhibited by thecompounds of this invention.

The compound according to the invention can be used for othertherapeutic purposes, for example:

-   -   a) the sensitisation of tumors to radiotherapy by administering        the compound according to the invention before, during or after        irradiation of the tumor for treating cancer, for example as        described in WO 00/01411;    -   b) treating athropathies such as rheumatoid arthritis,        osteoarthritis, juvenile arthritis, gout, polyarthritis,        psoriatic arthritis, ankylosing spondylitis and systemic lupus        erythematosus, for example as described in WO 00/01386;    -   c) inhibiting smooth muscle cell proliferation including        vascular proliferative disorders, atherosclerosis and        restenosis, for example as described in WO 98/55124;    -   d) treating inflammatory conditions such as ulcerative colitis,        Crohn's disease, allergic rhinitis, graft vs host disease,        conjunctivitis, asthma, ARDS, Behcets disease, transplant        rejection, uticaria, allergic dermatitis, alopecia areata,        scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes,        systemic lupus erythematosis, Kawasaki's disease, multiple        sclerosis, emphysema, cystic fibrosis and chronic bronchitis;    -   e) treating endometriosis, uterine fibroids, dysfunctional        uterine bleeding and endometrial hyperplasia;    -   f) treating ocular vascularisation including vasculopathy        affecting retinal and choroidal vessels;    -   g) treating pathologies resulting from heterotrimeric G protein        membrane fixation including diseases related to following        biological functions or disorders; smell, taste, light,        perception, neurotransmission, neurodegeneration, endocrine and        exocrine gland functioning, autocrine and paracrine regulation,        blood pressure, embryogenesis, viral infections, immunological        functions, diabetes, obesity;    -   h) inhibiting viral morphogenesis for example by inhibiting the        prenylation or the post-prenylation reactions of a viral protein        such as the large delta antigen of hepatitis D virus; and the        treatment of HIV infections;    -   i) treating polycystic kidney disease;    -   j) suppressing induction of inducible nitric oxide including        nitric oxide or cytokine mediated disorders, septic shock,        inhibiting apoptosis and inhibiting nitric oxide cytotoxicity;    -   k) treating malaria.

The compounds of present invention may be useful for the treatment ofproliferative diseases, both benign and malignant, wherein the K-ras Bisoform is activated as a result of oncogenic mutation.

Hence, the present invention discloses the compounds of formula (I) foruse as a medicine as well as the use of these compounds of formula (I)for the manufacture of a medicament for treating one or more of theabove-mentioned conditions.

For the treatment of the above conditions, the compound of the inventionmay be advantageously employed in combination with one or more othermedicinal agents such as anti-cancer agents

-   for example selected from platinum coordination compounds for    example cisplatin or carboplatin, taxane compounds for example    paclitaxel or docetaxel, camptothecin compounds for example    irinotecan or topotecan, anti-tumor vinca alkaloids for example    vinblastine, vincristine or vinorelbine, anti-tumor nucleoside    derivatives for example 5-fluorouracil, gemcitabine or capecitabine,    nitrogen mustard or nitrosourea alkylating agents for example    cyclophosphamide, chlorambucil, carmustine or lomustine, anti-tumor    anthracycline derivatives for example daunorubicin, doxorubicin or    idarubicin; HER2 antibodies for example trastzumab; and anti-tumor    podophyllotoxin derivatives for example etoposide or teniposide; and    antiestrogen agents including estrogen receptor antagonists or    selective estrogen receptor modulators preferably tamoxifen, or    alternatively toremifene, droloxifene, faslodex and raloxifene, or    aromatase inhibitors such as exemestane, anastrozole, letrazole and    vorozole.

For the treatment of cancer the compounds according to the presentinvention can administered to a patient as described above inconjunction with irradiation; such treatment is may be especiallybeneficial as farnesyl transferase inhibitors can act asradiosensitisers for example as described in International PatentSpecification WO 00/01411, enhancing the therapeutic effect of suchirradiation.

Irradiation means ionizing radiation and in particular gamma radiation,especially that emitted by linear accelerators or by radionuclides thatare in common use today. The irradiation of the tumor by radionuclidescan be external or internal.

Preferably, the administration of the farnesyl transferase inhibitorcommences up to one month, in particular up to 10 days or a week, beforethe irradiation of the tumor. Additionally, it is advantageous tofractionate the irradiation of the tumor and maintain the administrationof the farnesyl transferase inhibitor in the interval between the firstand the last irradiation session.

The amount of farnesyl protein transferase inhibitor, the dose ofirradiation and the intermittence of the irradiation doses will dependon a series of parameters such as the type of tumor, its location, thepatients' reaction to chemo- or radiotherapy and ultimately is for thephysician and radiologists to determine in each individual case.

The present invention also concerns a method of cancer therapy for ahost harboring a tumor comprising the steps of

-   -   administering a radiation-sensitizing effective amount of a        farnesyl protein transferase inhibitor according to the        invention before, during or after    -   administering radiation to said host in the proximity to the        tumor.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a particular compound, in base or acid addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which

-   additives do not cause a significant deleterious effect to the skin.    Said additives may facilitate the administration to the skin and/or    may be helpful for preparing the desired compositions. These    compositions may be administered in various ways, e.g., as a    transdermal patch, as a spot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that an effective amount would be from 0.01 mg/kg to 100mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg bodyweight. It may be appropriate to administer the required dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.5 to 500 mg, and in particular 1 mg to 200 mg of activeingredient per unit dosage form.

Experimental Part

Hereinafter “THF” means tetrahydrofuran, “DIPE” means diisopropyl ether,“EtOAc” means ethyl acetate, “DCM” means dichloromethane, “DMF” meansdimethylformamide and “BuLi” means n-butyl lithium, “BTEAC” meansbenzyltriethylammonium salt.

A. Preparation of the Intermediates

EXAMPLE A1

-   a) (4-aminophenyl)(4-chlorophenyl)-methanone (0.104 mol) and diethyl    (ethoxymethylene) malonate (0.114 mol) were stirred and heated at    130° C. overnight. The product was used without further    purification, yielding ethyl    2-[[[4-(4-chlorobenzoyl)phenyl]amino]carbonyl]-3-ethoxy-2-propenoate    (intermediate 1).-   b) A mixture of intermediate 1 (0.104 mol) in 1-1′-oxybis-benzene    (100 ml) was stirred and heated at 300° C. for 8 h. The mixture was    taken up in diethyl ether and the product was filtered off giving    14.6 g (39.5%) of ethyl    6-(4-chlorobenzoyl)-4-hydroxy-3-quinolinecarboxylate, melting    point >300° C. (intermediate 2).-   c) A mixture of intermediate 2 (0.051 mol) in sodium hydroxide    (35 ml) and water (100 ml) was stirred and refluxed overnight. The    mixture was cooled and poured onto H₂O. The pH of the mixture was    brought to 7 by adding HCl 6N and the mixture was filtered off. The    precipitate was washed with diethyl ether, taken up in DCM and    filtered off. The product was used without further purification,    yielding 16 g of 6-(4-chlorobenzoyl)-4-hydroxy-3-quinolinecarboxylic    acid (intermediate 3).-   d) Intermediate 3 (0.039 mol), Cu powder (0.031 mol) and quinoline    (0.465 mol) were stirred at 250° C. for 1 h 15 min. The mixture was    cooled, taken up in DCM and washed with water. The organic layer was    dried (MgSO₄), filtered off and evaporated till dryness. The residue    was taken up in diethyl ether, filtered off and dried, yielding 7.9    g (71%) of (4-chlorophenyl) (4-hydroxy-6-quinolinyl)methanone    (intermediate 4).-   e) A mixture of intermediate 4 (0.027 mol) in phosphoryl chloride    (100 ml) was stirred at 60° C. for 3 h. The mixture was evaporated,    the residue was taken up in DCM and basified with K₂CO₃ 10%. The    organic layer was dried (MgSO₄), filtered off and evaporated. The    product was used without further purification, yielding 7.6 g (91%)    of (4-chlorophenyl)(4-chloro-6-quinolinyl)methanone (intermediate    5).-   f) A mixture of phenol (0.026 mol) and sodium hydride (0.035 mol) in    DMF (15 ml) was stirred at room temperature for 1 h. intermediate 5    (0.025 mol) was added portionwise at room temperature, then DMF    (80 ml) was added dropwise and the mixture was stirred at room    temperature overnight. Water was added and the mixture was    evaporated. The residue was taken up in DCM and washed with water.    The organic layer was dried (MgSO₄), filtered off and evaporated    till dryness. The product was used without further purification,    yielding (4-chlorophenyl)(4-phenoxy-6-quinolinyl)methanone    (intermediate 6).-   g) A mixture of intermediate 6 (0.025 mol) and    3-chloro-benzenecarboperoxoic acid (0.05 mol) in DCM (150 ml) was    stirred at room temperature for 12 h. The mixture was basified with    a solution of K₂CO₃ 10% and extracted with DCM. The organic layer    was dried (MgSO₄), filtered off and evaporated till dryness. The    product was used without further purification, yielding    (4-chlorophenyl)(4-phenoxy-6-quinolinyl)methanone,N-oxide    (intermediate 7).-   h) A mixture of intermediate 7 (0.025 mol), 4-methyl-benzenesulfonyl    chloride (0.0312 mol) in K₂CO₃ 10% (100 ml) and DCM (100 ml) was    stirred at room temperature for 12 h. The organic layer was    decanted, dried (MgSO₄), filtered off and evaporated till dryness.    The residue was taken up in diethyl ether, the precipitate was    filtered off and dried, yielding 5 g (53%) of    6-(4-chlorobenzoyl)-4-phenoxy-2(1H)-quinolinone (intermediate 8).-   i) Sodium tetrahydroborate (0.0159 mol) was added portionwise at    room temperature to a solution of intermediate 8 (0.0133 mol) in    methanol (50 ml) and the mixture was stirred at room temperature for    1 h. Water was added and the mixture was evaporated. The precipitate    was filtered off, washed with water and diethyl ether and dried,    yielding 4 g (80%) of    (±)-6-[(4-chlorophenyl)hydroxymethyl]-4-phenoxy-2(1H)-quinolinone    (intermediate 9).

EXAMPLE A2

-   a) HCl/diethylether (0.15 mol) was added dropwise to a solution of    (4-aminophenyl)(4-chlorophenyl)-methanone (0.15 mol) in ethanol    (250 ml) and the mixture was stirred for 15 min. FeCl₃.6H₂O (0.255    mol) and then ZnCl₂ (0.015 mol) were added and the mixture was    stirred at 65° C. for 30 min. 3-buten-2-one (0.15 mol) was added and    the mixture was stirred at 80° C. overnight. The mixture was poured    into ice and basified with NH₄OH. The suspension was filtered    through celite and the filtrate was extracted with DCM. The organic    layer was dried (MgSO₄), filtered off and evaporated till dryness.    The product was used without further purification, yielding 43.1 g    (100%) of (4-chlorophenyl)(4-methyl-6-quinolinyl)-methanone, mp    114° C. (intermediate 10).-   b) A mixture of intermediate 10 (0.15 mol), 1,2-ethanediol (0.54    mol) and paratoluenesulfonic acid (0.18 mol) in toluene (600 ml) was    stirred and refluxed in a Dean Stark apparatus overnight. The    mixture was cooled, basified with K₂CO₃ 10% and extracted with DCM.    The organic layer was dried (MgSO₄), filtered off and evaporated    till dryness. The residue was purified by column chromatography over    silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 99.75/0.25/0.2) (35–70 μm).    The pure fractions were collected and evaporated, yielding 35 g    (73%) of 6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-4-methyl-quinoline    (intermediate 11).-   c) BuLi (0.0612 mol) was added dropwise to a cooled (−20° C.)    solution of N,N,N′,N′-tetramethyl-1,2-ethanediamine (0.0612 mol) and    N-(1-methylethyl)-2-propanamine (0.0612 mol) in THF (20 ml) and the    mixture was stirred at −20° C. for 15 min. A solution of    intermediate 11 (0.0408 mol) in THF (45 ml) was added slowly and the    mixture was stirred at −20° C. for 1 h.    1-chloro-3-(chloromethyl)-benzene (0.049 mol) was added and the    mixture was stirred at room temperature overnight. The mixture was    quenched with water and extracted with EtOAc. The organic layer was    dried (MgSO₄), filtered off and evaporated till dryness. The residue    was purified by column chromatography over silica gel (eluent:    cyclohexane/EtOAc 70/30) (15–40 μm). The pure fractions were    collected, yielding 3.9 g of    6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-4-[2-(3-chlorophenyl)ethyl]-quinoline    (intermediate 12a) and 3.9 g of    4-[2-(3-chlorophenyl)-1-[(3-chlorophenyl)methyl]ethyl]-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-quinoline    (intermediate 12b).-   d) 3-chlorobenzenecarboperoxoic acid (0.042 mol) was added to a    mixture of intermediate 12a (0.021 mol) in DCM (100 ml). The mixture    was stirred at room temperature for 1 hour. K₂CO₃ 10% was added. The    mixture was extracted with DCM. The organic layer was separated,    dried (MgSO₄), filtered and the solvent was evaporated. The product    was used without further purification, yielding    6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-4-[2-(3-chlorophenyl)ethyl]-,    1-oxide quinoline (intermediate 13).-   e) K₂CO₃ 10% (150 ml) and then 4-methyl-benzenesulfonyl chloride    (0.0315 mol) were added to a mixture of intermediate 13 (0.021 mol)    in DCM (150 ml). The mixture was stirred at room temperature for 1    hour. Diethylether was added. The mixture was decanted and extracted    with DCM. The organic layer was separated, dried (MgSO₄), filtered    and the solvent was evaporated. The residue was crystallized from    diethylether. The precipitate was filtered off and dried, yielding 7    g (71%) of    6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-4-[2-(3-chlorophenyl)ethyl]-2(1H)-quinolinone    (intermediate 14).-   f) BTEAC (0.0015 mol) and then iodomethane (0.03 mol) were added to    a mixture of intermediate 14 (0.015 mol) in concentrated sodium    hydroxide (50 ml) and THF (50 ml). The mixture was stirred at room    temperature for the weekend. Water was added and the mixture was    extracted with DCM. The organic layer was dried (MgSO₄), filtered    and the solvent was evaporated, yielding 7.5 g (>100%) of    6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone    (intermediate 15).-   g) A mixture of intermediate 15 (0.015 mol) in HCl 3N (70 ml) and    THF (70 ml) was stirred and refluxed overnight. Water was added and    the mixture was extracted with DCM. The organic layer was separated,    dried (MgSO₄), filtered, and the solvent was evaporated. The residue    was crystallized from acetonitrile. The precipitate was filtered    off, washed with DIPE and dried, yielding 4.5 g (69%) of    6-(4-chlorobenzoyl)-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone    (intermediate 16).

EXAMPLE A3

-   a) A mixture of 2-(4-chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane    (described in WO 97/16443) (0.164 mol) in methanol (500 ml) was    hydrogenated under a 3 bar pressure for 3 hours with Raney Nickel    (50 g) as a catalyst. After uptake of H₂ (3 equiv), the catalyst was    filtered through celite and the filtrate was evaporated till    dryness. The reaction was carried out again using the same    quantities. The residues were combined and used without further    purification, yielding 88 g (97.3%) of    4-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-benzenamine (intermediate    17).-   b) Intermediate 17 (0.32 mol) and (ethoxymethylene)-1-propanedioic    acid, diethyl ester (0.352 mol) were stirred at 130° C. overnight    using a Dean-Stark apparatus and then cooled to room temperature.    DCM was added. The organic solution was washed with water, dried    (MgSO₄), filtered and the solvent was evaporated till dryness. The    residue (160 g) was purified by column chromatography over silica    gel (eluent: cyclohexane/EtOAc 75/25; 15–40 μm). The pure fractions    were collected and the solvent was evaporated, yielding 120 g    (82.7%) of    2-[[[4-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl]amino]carbonyl]-3-ethoxy-(2Z)-2-propenoic    acid ethyl ester (intermediate 18).-   c) A mixture of intermediate 18 (0.09 mol) in 1,1′-oxybis-benzene    (110 ml) was stirred at 300° C. for 20 hours and then cooled. DIPE    and petroleum ether were added. The precipitate was filtered off,    washed and dried. The reaction was carried out again using the same    quantities. The residues were combined and purified by column    chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 96/4; 15–40    μm). The pure fractions were collected and the solvent was    evaporated, to give 11.5 g of    6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-4-hydroxy-3-quinolinecarboxylic    acid ethyl ester (intermediate 19).-   d) A mixture of intermediate 19 (0.0175 mol) in phosphoryl chloride    (70 ml) was stirred at 60° C. for 2 hours and then cooled. The    solvent was evaporated till dryness. The residue was taken up in    DCM. The organic solution was washed with K₂CO₃ 10%, dried (MgSO₄),    filtered and the solvent was evaporated. The product was used    without further purification, yielding 8.1 g of    4-chloro-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-quinolinecarboxylic    acid ethyl ester (intermediate 20).-   e) Sodium hydride (0.0298 mol) was added at 10° C. under N₂ flow to    a solution of 3-chloro-phenol (0.0193 mol) in DMF (50 ml). The    mixture was stirred for 1 hour. A solution of intermediate 20    (0.0175 mol) in DMF (50 ml) was added dropwise. The mixture was    stirred at room temperature for 3 hours, poured out into water and    extracted with EtOAc. The organic layer was separated, washed with    water, dried (MgSO₄), filtered and the solvent was evaporated. The    product was used without further purification, yielding 9.01 g of    4-(3-chlorophenoxy)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-quinolinecarboxylic    acid, ethyl ester (intermediate 21).-   f) 3-chlorobenzenecarboperoxoic acid was added at room temperature    to a mixture of intermediate 21 (0.0175 mol) in DCM (100 ml). The    mixture was stirred at room temperature overnight. K₂CO₃ 10% was    added. The organic layer was separated, dried (MgSO₄), filtered and    used as such without further purification, yielding    4-(3-chlorophenoxy)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-quinolinecarboxylic    acid, ethyl ester, 1-oxide (intermediate 22).-   g) K₂CO₃ 10% (150 ml) was added to a solution of intermediate 22    (0.0175 mol) in DCM (150 ml). Then 4-methyl-benzenesulfonyl chloride    (0.0219 mol) was added. The mixture was stirred at room temperature    for 4 hours. The organic layer was separated, washed with water,    dried (MgSO₄), filtered and the solvent was evaporated. The product    was used without further purification, yielding 13 g of    4-(3-chlorophenoxy)-6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-1,2-dihydro-2-oxo-3-quinolinecarboxylic    acid ethyl ester (intermediate 23).-   h) A mixture of intermediate 23 (0.0175 mol) in HCl 3N (140 ml) and    THF (30 ml) was stirred and refluxed for 4 hours, then cooled,    poured out into water and extracted with EtOAc. The organic layer    was separated, washed with K₂CO₃ 10%, dried (MgSO₄), filtered and    the solvent was evaporated. The residue (11.4 g) was purified by    column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH    97.5/2.5; 20–45 μm). The pure fractions were collected and the    solvent was evaporated yielding 6.4 g (76%) of    6-(4-chlorobenzoyl)-4-(3-chlorophenoxy)-1,2-dihydro-2-oxo-3-quinolinecarboxylic    acid, ethyl ester (intermediate 24).-   i) Sodium tetrahydroborate (0.034 mol) was added portionwise at    10° C. to a solution of intermediate 24 (0.017 mol) in methanol (100    ml). The mixture was stirred for 1 hour. Water was added and the    mixture was extracted with DCM. The organic layer was separated,    dried (MgSO₄), filtered and the solvent was evaporated, yielding 7.5    g (91%) of    4-(3-chlorophenoxy)-6-[(4-chlorophenyl)hydroxymethyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylic    acid, ethyl ester (intermediate 25).-   j) A mixture of intermediate 25 (0.0155 mol) in thionyl chloride    (75 ml) was stirred and refluxed for 24 hours and then cooled. The    solvent was evaporated till dryness. The product was used without    further purification, yielding    6-[chloro(4-chlorophenyl)methyl]-4-(3-chlorophenoxy)-1,2-dihydro-2-oxo-3-quinolinecarboxylic    acid, ethyl ester (intermediate 26).

EXAMPLE A4

-   a) A mixture of intermediate 12a (0.0087 mol) and intermediate 12b    (0.0087 mol) in HCl 3N (80 ml) and methanol (30 ml) was stirred and    refluxed overnight. The mixture was poured into ice, basified with    NH₄OH and extracted with DCM. The organic layer was dried (MgSO₄),    filtered off and evaporated till dryness. The residue was purified    by column chromatography over silica gel (eluent: CH₂Cl₂/EtOAc 96/4)    (15–40 μm). The pure fractions were collected and evaporated,    yielding 2.4 g (34%)    (4-chlorophenyl)[4-[2-(3-chlorophenyl)ethyl]-6-quinolinyl]-methanone    (intermediate 27a) and 2.8 g (44%) of    (4-chlorophenyl)[4-[2-(3-chlorophenyl)-1-[(3-chlorophenyl)methyl]ethyl]-6-quinolinyl]-methanone    (intermediate 27b).-   b) 3-chloro-benzenecarboperoxoic acid (0.0129 mol) was added to a    solution of intermediate 27a (0.0059 mol) in DCM (25 ml) and the    mixture was stirred at room temperature for 1 h. A solution of K₂CO₃    10% was added and the mixture was extracted with DCM. The organic    layer was dried (MgSO₄), filtered off and evaporated till 50 ml of    the solvent which was used without further purification, yielding    (quant.) of    (4-chlorophenyl)[4-[2-(3-chlorophenyl)ethyl]-1-oxido-6-quinolinyl]-methanone    (intermediate 28).-   c) A mixture of intermediate 28 (0.0337 mol) in phosphoryl chloride    (100 ml) was stirred and refluxed for 30 min. The solvent was    evaporated till dryness. The residue was taken up in ice and NH₄OH.    The mixture was stirred for 3 hours and extracted with DCM. The    organic layer was separated, dried (MgSO₄), filtered and the solvent    was evaporated till dryness. The residue (14.2 g) was purified by    column chromatography over silica gel (eluent: cyclohexane/EtOAc    90/10; 20–45 μm). The pure fractions were collected and the solvent    was evaporated. The residue was taken up in DCM and a small amount    of methanol. The precipitate was filtered off and dried, yielding    7.45 g (50%) of    [2-chloro-4-[2-(3-chlorophenyl)ethyl]-6-quinolinyl](4-chlorophenyl)-methanone,    melting point 180° C. (intermediate 29).-   d) BuLi 1.6M in hexane was added dropwise at −70° C. to a mixture of    1-methyl-1H-imidazole (0.0098 mol) in TBF (15 ml). The mixture was    stirred for 30 min. ClSiEt₃ (0.0098 mol) was added. The mixture was    brought slowly to 10° C. and cooled again to −70° C. BuLi 1.6M in    hexane (6.1 ml) was added dropwise. The mixture was stirred for 1    hour, brought quickly to −15° C. and cooled again to −70° C. A    solution of intermediate 29 (0.0082 mol) in THF (40 ml) was added    dropwise. The mixture was stirred at −50° C., then hydrolyzed and    extracted with EtOAc. The organic layer was separated, dried    (MgSO₄), filtered and the solvent was evaporated till dryness. The    residue (5.4 g) was purified by column chromatography over silica    gel (eluent: toluene/2-propanol/NH₄OH 87/13/0.5; 15–40 μm). The pure    fractions were collected and the solvent was evaporated, yielding    2.15 g (50%) of    2-chloro-α-(4-chlorophenyl)-4-[2-(3-chlorophenyl)ethyl]-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol    (intermediate 30).

EXAMPLE A5

-   a) BuLi (0.058 mol) was added dropwise at −20° C. to a solution of    N-(1-methylethyl)-2-propanamine (0.058 mol) and    N,N,N′,N′-tetramethyl-1,2-ethanediamine (0.058 mol) in THF (95 ml)    and the mixture was stirred at −20° C. for 15 min. A solution of    intermediate 11 (0.0387 mol) in THF (13 ml) was added dropwise at    −20° C. and the mixture was stirred at −20° C. for 1 h.    (Chloromethyl)-benzene (0.0464 mol) was added at −20° C. and the    mixture was heated till room temperature. The mixture was hydrolysed    and evaporated till dryness. The residue was taken up in DCM and    K₂CO₃ 10%. The organic layer was dried (MgSO₄), filtered off and    evaporated till dryness. The residue was purified by column    chromatography over silica gel (eluent: cyclohexane/EtOAc 60/40)    (35–70 μm). The pure fractions were collected and evaporated,    yielding 9 g (56%) of    6-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-4-(2-phenylethyl)-quinoline    (intermediate 31).-   b) A mixture of intermediate 31 (0.0216 mol) in HCl 3N (50 ml) and    methanol (50 ml) was stirred at 60° C. overnight. The mixture was    basified with NH₄OH and extracted with DCM. The organic layer was    dried (MgSO₄), filtered off and evaporated till dryness. The product    was used without further purification, yielding 6.5 g (80%) of    (4-chlorophenyl)[4-(2-phenylethyl)-6-quinolinyl]-methanone    (intermediate 32).-   c) A mixture of intermediate 32 (0.0175 mol) and    3-chloro-benzenecarboperoxoic acid (0.035 mol) in DCM (100 ml) was    stirred at room temperature for 3 h. The mixture was basified with a    solution of K₂CO₃ 10%. The organic layer was dried (MgSO₄), filtered    off and evaporated till dryness. The product was used without    further purification, yielding 6.7 g (100%) of    (4-chlorophenyl)[1-oxido-4-(2-phenylethyl)-6-quinolinyl]-methanone    (intermediate 33).-   d) A mixture of intermediate 33 (0.0242 mol) in phosphoryl chloride    (100 ml) was stirred and refluxed for 1 hour. The solvent was    evaporated till dryness. The residue was taken up in DCM. The    mixture was poured out into ice water and basified with NH₄OH. The    organic layer was separated, dried (MgSO₄), filtered and the solvent    was evaporated till dryness. The residue was crystallized from    2-propanone. The precipitate was filtered off, washed with diethyl    ether and dried, yielding 4.8 g (49%) of    (4-chlorophenyl)[2-chloro-4-(2-phenylethyl)-6-quinolinyl]-methanone    (intermediate 34).-   e) BuLi 1.6M in hexane (8.9 ml) was added dropwise at −70° C. under    N₂ flow to a mixture of 1-methyl-1H-imidazole (0.0118 mol) in THF    (20 ml). The mixture was stirred for 30 min. ClSiEt₃ (0.0142 mol)    was added. The mixture was brought slowly to room temperature and    cooled again to −70° C. C (8.9 ml) was added dropwise. The mixture    was stirred for 1 hour, brought quickly to −20° C. and cooled again    to −70° C. A solution of intermediate 34 (0.0118 mol) in THF (50 ml)    was added dropwise. The mixture was stirred at −70° C. for 1 hour,    hydrolyzed and extracted with DCM. The organic layer was separated,    dried (MgSO₄), filtered and the solvent was evaporated till dryness.    The residue (8.8 g) was purified by column chromatography over    silica gel (eluent: toluene/2-propanol/NH₄OH 85/15/0.5; 20–45 μm).    Two pure fractions were collected and their solvents were    evaporated, yielding 1.7 g (35%) of starting material intermediate    34 and 2.3 g (40%) of    2-chloro-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-4-(2-phenylethyl)-6-quinolinemethanol    (intermediate 35).

EXAMPLE A6

-   a) 4-Methylbenzenesulfonate (0.0364 mol) and then trimethoxy-methane    (3.636 mol) were added to a mixture of 5-bromo-1H-indole-2,3-dione    (0.364 mol) in methanol (1200 ml). The mixture was stirred and    refluxed for 3 hours, poured out into ice water and extracted with    DCM. The organic layer was separated, dried (MgSO₄), filtered and    the solvent was evaporated till dryness. The residue (125 g) was    purified by column chromatography over silica gel (eluent:    CH₂Cl₂/CH₃OH 99/1 and 98/2; 20–45 μm). The pure fractions were    collected and the solvent was evaporated. The residue (50 g, 52%)    was taken up in DIPE. The precipitate was filtered off and dried,    yielding 45 g (45%) of    5-bromo-1,3-dihydro-3,3-dimethoxy-2H-indol-2-one (intermediate 36).-   b) BuLi 1.6M in hexane (0.127 mol) was added dropwise at −70° C. to    a mixture of intermediate 36 (0.0577 mol) in THF (150 ml). The    mixture was stirred for 1 hour. A solution of    4-chloro-N-methoxy-N-methyl-benzamide (0.0634 mol) in THF (30 ml)    was added dropwise. The mixture was brought to room temperature,    stirred at room temperature for 3 hours, hydrolysed and extracted    with DCM. The organic layer was separated, dried (MgSO₄), filtered    and the solvent was evaporated till dryness. The residue was    crystallized from 2-propanone and diethyl ether. The precipitate was    filtered off, washed with DIPE and dried, yielding 8.05 g (42%) of    5-(4-chlorobenzoyl)-1,3-dihydro-3,3-dimethoxy-2H-indol-2-one,    melting point 170° C. (intermediate 37).-   c) A mixture of intermediate 37 (0.151 mol) in HCl 3N (300 ml) and    THF (300 ml) was stirred and refluxed overnight and then cooled. The    solvent was evaporated partially. The precipitate was filtered off,    washed several times with diethyl ether and dried with toluene in    vacuo, yielding 40 g (93%) of    5-(4-chlorobenzoyl)-1H-indole-2,3-dione (intermediate 38).-   d) A mixture of intermediate 38 (0.119 mol) in acetic anhydride    (150 ml) was stirred and refluxed for 1 hour and then cooled. DIPE    was added. The precipitate was filtered off, washed several times    with DIPE and dried, yielding 35.5 g (91%) of    1-acetyl-5-(4-chlorobenzoyl)-1H-indole-2,3-dione (intermediate 39).-   e) A mixture of intermediate 39 (0.078 mol), propanedioic acid    (0.094 mol) and NaOAc (0.0094 mol) in HOAc (140 ml) was stirred and    refluxed for 48 hours and then cooled. Water was added. The    precipitate was filtered off, washed several times with water and    dried with toluene in vacuo. The reaction was carried out three    times. The residues were combined, yielding 72.9 g (95%) of    6-(4-chlorobenzoyl)-1,2-dihydro-2-oxo-4-quinolinecarboxylic acid,    melting point >260° C. (intermediate 40).-   f) 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride    (0.037 mol), 1-hydroxybenzotriazole (0.037 mol) and triethylamine    (0.037 mol) were added at room temperature to a solution of    intermediate 40 (0.0244 mol) and 3-chloro-benzenamide (0.037 mol) in    THF (240 ml) under N₂ flow. The mixture was stirred at room    temperature for 24 hours, poured out into ice water and extracted    with EtOAc. The organic layer was separated, dried (MgSO₄),    filtered, and the solvent was evaporated. The residue (11 g) was    purified by column chromatography over silica gel (eluent:    CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5; 15–35 μm). The pure fractions were    collected and the solvent was evaporated, yielding: 3.2 g (30%).    Part of this fraction (0.2 g) was crystallized from CH₂Cl₂/diethyl    ether. The precipitate was filtered off and dried, yielding 0.16 g    of    6-(4-chlorobenzoyl)-N-(3-chlorophenyl)-1,2-dihydro-2-oxo-4-quinolinecarboxamide    hydrate (1:1), melting point 214° C. (intermediate 41).-   g) A mixture of intermediate 41 (0.0059 mol), iodomethane (0.0088    mol) and BTEAC (0.0003 mol) in NaOH 3N (30 ml) and THF (30 ml) was    stirred at room temperature for 6 hours, poured out into water and    extracted with EtOAc. The organic layer was separated, dried    (MgSO₄), filtered, and the solvent was evaporated. The residue    (2.4 g) was purified by column chromatography over silica gel    (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98.5/1.5 to 95/5/0.2; 15–40 μm). The    pure fractions were collected and the solvent was evaporated,    yielding: 0.98 g (35%) of a residue. A sample of the residue    (0.75 g) was crystallized from CH₃CN/diethyl ether. The precipitate    was filtered off and dried, yielding 0.585 g of    6-(4-chlorobenzoyl)-N-(3-chlorophenyl)-1,2-dihydro-N,1-dimethyl-2-oxo-4-quinolinecarboxamide,    melting point 184° C. (intermediate 42).

EXAMPLE A7

-   a) A mixture of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide    hydrochloride (0.037 mol), 1-hydroxybenzotriazole (0.037 mol) and    triethylamine (0.037 mol) was added at room temperature to a    solution of intermediate 40 (0.0244 mol) and 3-methyl-benzenamine    (0.037 mol) in THF (240 ml) under N₂ flow. The mixture was stirred    at room temperature for 24 hours, poured out into ice water and    extracted with EtOAc. The organic layer was separated, dried    (MgSO₄), filtered, and the solvent was evaporated. Part (0.2 g) of    the residue (7.3 g, 72%) was crystallized from CH₂Cl₂/diethyl ether.    The precipitate was filtered off and dried, yielding 0.16 g of    6-(4-chlorobenzoyl)-1,2-dihydro-N-(3-methylphenyl)-2-oxo-4-quinolinecarboxamide,    melting point 230° C. (intermediate 43).-   b) A mixture of intermediate 43 (0.017 mol), iodomethane (0.034 mol)    and BTEAC (0.0008 mol) in NaOH 3N (70 ml) and THF (70 ml) was    stirred at room temperature for 5 hours and poured out into ice    water. EtOAc was added. The mixture was filtered over celite. The    organic layer was separated, dried (MgSO₄), filtered, and the    solvent was evaporated. The residue was taken up in CH₂Cl₂/diethyl    ether. The precipitate was filtered off and discarded. The filtrate    was evaporated and the residue (4.1 g) was purified by column    chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98.5/1.5; 15–40    μm). The pure fractions were collected and the solvent was    evaporated, yielding: 2.18 g of a residue which was further purified    by column chromatography over silica gel (eluent: toluene/CH3OH    95/5; 15–40 μm). The pure fractions were collected and the solvent    was evaporated, yielding: 1.9 g (25%) of    6-(4-chlorobenzoyl)-1,2-dihydro-N,1-dimethyl-N-(3-methylphenyl)-2-oxo-4-quinolinecarboxamide,    melting point 91° C. (intermediate 44).    B. Preparation of the Final Compounds

EXAMPLE B1

A mixture of intermediate 9 (0.0106 mol), 1,1′-carbonyldiimidazole(0.0318 mol) and NaH (0.0001 mol) in THF (60 ml) was stirred at roomtemperature for 30 min. The mixture was poured into water and extractedwith EtOAc. The organic layer was dried (MgSO₄), filtered off andevaporated till dryness. The residue was purified by columnchromatography over silica gel (eluent: toluene/2-propanol/NH₄OH90/10/0.1) (15–40 μm). The pure fractions were collected and evaporated.The residue (2.1 g) was crystallized from 2-propanone/DIPE, yielding 1.2g (46%) of(±)-6-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-4-phenoxy-2(1H)-quinolinone,melting point 233.3° C.

EXAMPLE B2

A mixture of 1-methyl-1H-imidazole (0.0206 mol) in THF (35 ml) wascooled to −70° C. under N₂ flow. BuLi 1.6M (12.9 ml) was added dropwise.The mixture was stirred at −70° C. for 30 min. Chlorotriethyl-silane(0.0206 mol) was added. The mixture was allowed to warm to 10° C. andthen cooled to −70° C. BuLi 1.6M (12.9 ml) was added dropwise. Themixture was stirred at −70° C. for 1 hour, then brought to −15° C.,cooled to −70° C. and poured out under N₂ flow into a solution ofintermediate 16 (0.00825 mol) in THF (18 ml). The mixture was stirred at−70° C. for 30 min, then hydrolyzed, extracted with EtOAc and decanted.The organic layer was dried (MgSO₄), filtered and the solvent wasevaporated. The residue (9 g) was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 15–40 μm). The purefractions were collected and their solvents were evaporated. The residuewas crystallized from 2-propanone/CH₃CN/DIPE. The precipitate wasfiltered off and dried, yielding 1.9 g of4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,mp 190° C.

EXAMPLE B3

-   a) Thionyl chloride (30 ml) was cooled on an ice bath and then    poured out cold on    4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone    (see Example B2) (0.0025 mol). The mixture was stirred at 40° C. for    2 hours. The solvent was evaporated till dryness. The product was    used without further purification, yielding    6-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone    hydrochloride.-   b) NH₃/2-propanol saturated (80 ml) was added dropwise at 10° C. to    a mixture of    6-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone    (see Example B3a) (0.017 mol) in THF (80 ml). The mixture was    stirred at room temperature for 3 hours, hydrolyzed and extracted    with DCM. The organic layer was separated, dried (MgSO₄), filtered    and the solvent was evaporated till dryness. The residue (14 g) was    purified by column chromatography over silica gel (eluent:    cyclohexane/2-propanol/NH₄OH 64/35/1 and 48/50/2; 15–35 μm). The    desired fractions were collected and the solvent was evaporated,    yielding 7.2 g of residue which was crystallized from CH₃CN. The    precipitate was filtered off and dried. The residue (5.3 g) was    purified by column chromatography (eluent: CH₃OH/(NH₄OAc 1% in H₂O)    80/20). The pure fractions were collected and the solvent was    evaporated. The residue (3.8 g) was crystallized from CH₃CN. The    precipitate was filtered off and dried, yielding 3.2 g (36%) of    6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone,    melting point 165° C.

EXAMPLE B4

A mixture of intermediate 26 (0.0155 mol), 2-phenyl-1H-imidazole (0.0233mol) and K₂CO₃ (0.0465 mol) in acetonitrile (200 ml) was stirred andrefluxed for 6 hours and then cooled. The solvent was evaporated tilldryness. The residue was taken up in DCM. The organic layer wasseparated, washed with water, dried (MgSO₄), filtered and the solventwas evaporated. The residue (10.7 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.5;15–40 μm). Two pure fractions (F1 and F2) were collected and theirsolvents were evaporated, yielding 1.35 g F1 (14%) of4-(3-chlorophenoxy)-6-[(4-chlorophenyl)(2-phenyl-1H-imidazol-1-yl)methyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylicacid, ethyl ester and 0.8 g (8%) of F2. F2 was crystallized from2-propanone and diethyl ether. The precipitate was filtered off anddried, yielding 0.65 g (7%) of4-(3-chlorophenoxy)-6-[(4-chlorophenyl)(2-phenyl-1H-imidazol-5-yl)methyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylicacid ethyl ester, melting point 189° C.

EXAMPLE B5

A solution of4-(3-chlorophenoxy)-6-[(4-chlorophenyl)(2-phenyl-1H-imidazol-1-yl)methyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylicacid, ethyl ester (see Example B4) (0.00221 mol) in THF (12 ml) wasadded dropwise at 5° C. under N₂ flow to a mixture of LiAlH₄ (0.00443mol) in THF (10 ml). The mixture was stirred at 5° C. for 1 hour,brought to room temperature, stirred at room temperature for 2 hours andthen cooled. EtOAc was added dropwise. The mixture was hydrolyzedslowly, filtered over celite and washed with EtOAc. The filtrate wasextracted with EtOAc. The organic layer was separated, washed withwater, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (1.25 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1; 15–40 μm). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom 2-propanone and diethyl ether. The precipitate was filtered off anddried, yielding 0.72 g (57%) of4-(3-chlorophenoxy)-6-[(4-chlorophenyl)(2-phenyl-1H-imidazol-1-yl)methyl]-3-(hydroxymethyl)-2(1H)-quinolinone,melting point 246° C.

EXAMPLE B6

Sodium azide (0.0123 mol) was added to a mixture of intermediate 30(0.0041 mol) in DMF (50 ml). The mixture was stirred at 140° C. for 5hours and poured out into water. The precipitate was filtered off andtaken up in DCM. The organic solution was dried (MgSO₄), filtered andthe solvent was evaporated till dryness. The residue (2.2 g) waspurified by column chromatography over silica gel (eluent:toluene/2-propanol/NH₄OH 90/10/0.6; 15–40 μm). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom 2-propanone and CH₃CN. The precipitate was filtered off and dried,yielding 1 g (46%) ofα-(4-chlorophenyl)-5-[2-(3-chlorophenyl)ethyl]-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinoline-7-methanol,melting point 242° C.

EXAMPLE B7

-   a) A mixture of    α-(4-chlorophenyl)-5-[2-(3-chlorophenyl)ethyl]-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinoline-7-methanol    (see Example B6) (0.00302 mol) in thionyl chloride (15 ml) was    stirred at room temperature for 4 hours. The solvent was evaporated    till dryness. The product was used without further purification,    yielding    7-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-[2-(3-chlorophenyl)ethyl]-tetrazolo[1,5-α]quinoline    hydrochloride (1:1)-   b) 2-propanol/NH₃ saturated (10 ml) was added dropwise at 0° C. to a    mixture of    7-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-[2-(3-chlorophenyl)ethyl]-tetrazolo[1,5-α]quinoline    hydrochloride (1:1) (see Example B7a) (0.00302 mol) in THF (20 ml).    The mixture was stirred at 0° C. for 30 min, hydrolized and    extracted with DCM. The organic layer was separated, dried (MgSO₄),    filtered and the solvent was evaporated till dryness. The residue    (1.65 g) was purified by column chromatography over silica gel    (eluent: toluene/2-propanol/NH₄OH 90/10/0.2; 15–40 μm). The pure    fractions were collected and the solvent was evaporated. The residue    was dissolved in CH₃CN and converted into the ethanedioic acid salt    (1:2). The precipitate was filtered off and dried, yielding 0.18 g    (8.2%) of    α-(4-chlorophenyl)-5-[2-(3-chlorophenyl)ethyl]-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinoline-7-methanamine,    melting point 160° C.

EXAMPLE B8

A mixture of intermediate 35 (0.0047 mol) and sodium azide (0.0141 mol)in DMF (25 ml) was stirred at 140° C. for 3 hours and poured out intoice water. The preciptate was filtered off, washed with water and takenup in DCM. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated till dryness. The residue was crystallizedfrom 2-propanone and DIPE. The precipitate was filtered off and dried,yielding 2 g (86%) ofα-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-(2-phenylethyl)-tetrazolo[1,5-α]quinoline-7-methanol,melting point 247° C.

EXAMPLE B9

Sulfuric acid concentrated (0.8 ml) was added to a mixture ofα-(4-chlorophenyl)-5-[2-(3-chlorophenyl)ethyl]-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinoline-7-methanol(see Example B6) (0.0019 mol) in acetonitrile (10 ml). The mixture wasstirred at 80° C. for 3 hours, then poured out into K₂CO₃ 10% andextracted with DCM. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated till dryness. The residue wascrystallized from diethyl ether. The precipitate was filtered off anddried, yielding 0.51 g (47%) ofN-[(4-chlorophenyl)[5-[2-(3-chlorophenyl)ethyl]tetrazolo[1,5-α]quinolin-7-yl](1-methyl-1H-imidazol-5-yl)methyl]-acetamide,melting point 200° C.

EXAMPLE B10

Sulfuric acid concentrated (0.5 ml) was added to a mixture ofα-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-(2-phenylethyl)-tetrazolo[1,5-α]quinoline-7-methanol(see Example B8) (0.00202 mol) in acetonitrile (10 ml). The mixture wasstirred and refluxed for 2 hours, poured out on ice and a concentratedNH₄OH solution and extracted with EtOAc. The mixture was stirred for 30min. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated till dryness. The residue was crystallized fromdiethyl ether. The precipitate was filtered off and dried, yielding 0.45g (42%) ofN-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)[5-(2-phenylethyl)tetrazolo[1,5-α]quinolin-7-yl]methyl]-acetamide,melting point 170° C.

EXAMPLE B11

BuLi 1.6M (1.6 ml, 0.0025 mol) was added dropwise at −70° C. to asolution of 1-methyl-1H-imidazole (0.0025 mol) in THF (5 ml) under N₂flow. The mixture was stirred for 10 minutes. ClSiEt₃ (0.0026 mol) wasadded. The mixture was stirred for 10 minutes. BuLi 1.6M (1.4 ml, 0.0022mol) was added. The mixture was stirred for 15 minutes. A solution ofintermediate 42 (0.00143 mol) in THF (15 ml) was added. The mixture wasstirred at −70° C. for 1 hours and 30 minutes, poured out into NH₄Cl 10%and extracted with EtOAc. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue (1.15 g)was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 94/6/0.1; 15–40 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.3 g) wascrystallized from 2-propanone. The precipitate was filtered off anddried, yielding 0.21 g (27%) ofN-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,2-dihydro-N,1-dimethyl-2-oxo-4-quinolinecarboxamide,melting point 218° C.

EXAMPLE B12

BuLi (4.4 ml, 0.0071 mol) was added dropwise at −70° C. to a solution of1-methyl-1H-imidazole (0.0071 mol) in THF (15 ml) under N₂ flow. Themixture was stirred for 10 minutes. Chlorotriethyl-silane (0.0073 mol)was added. The mixture was stirred for 10 minutes. BuLi (3.9 ml, 0.0063mol) was added. The mixture was stirred for 10 minutes. A solution ofintermediate 44 (0.004 mol) in THF (20 ml) was added. The mixture wasstirred at −70° C. for 1 hour and 30 minutes, poured out into NH₄Cl 10%and extracted with EtOAc. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated. The residue (3.8 g)was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 94/6/0.5; 15–40 μm). The pure fractions werecollected and the solvent was evaporated, yielding 1.1 g of a residuewhich was crystallized from petroleum ether. The precipitate wasfiltered off and dried, yielding 0.92 g (43%) of6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,2-dihydro-N,1-dimethyl-N-(3-methylphenyl)-2-oxo-4-quinolinecarboxamide,melting point 185° C.

EXAMPLE B13

2,2,2-Trichloroethyl-carbonochloridic acid ester (0.0072 mol) was addedat room temperature to a mixture of6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone,obtained in Example B3 (0.0014 mol) in DMF (10 ml). The mixture wasstirred for 1 hour, poured out into ice water, basified with K₂CO₃ andextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue was crystallizedfrom CH₃CN/DIPE. The precipitate was filtered off and dried, yielding0.54 g (65%) ofN′-[(Z)-(4-chlorophenyl)[4-[2-(3-chlorophenyl)ethyl]-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-N,N-dimethyl-methanimidamide(E), melting point 198° C.

EXAMPLE B14

BuLi (0.0105 mol) was added dropwise at −70° C. to a mixture of3-bromo-pyridine (0.0105 mol) in diethyl ether (15 ml) under N₂ flow.The mixture was stirred at −70° C. for 15 minutes. A solution ofintermediate 16 (0.0053 mol) in THF (25 ml) was added at −70° C. Themixture was stirred at −70° C. for 30 minutes, poured out into ice waterand extracted with EtOAc. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1; 15–40 μm). The pure fractions werecollected and the solvent was evaporated, yielding 1.5 g (55%) of4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy-3-pyridinylmethyl]-1-methyl-2(1H)-quinolinone,melting point 115° C.

EXAMPLE B15

-   a) A mixture of    4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy-3-pyridinylmethyl]-1-methyl-2(1H)-quinolinone,    obtained in Example B14 (0.0026 mol) in SOCl₂ (15 ml) was stirred at    room temperature for 3 hours. The solvent was evaporated till    dryness. The residue was taken up in DCM. The solvent was    evaporated, yielding 1.5 g of    6-[chloro(4-chlorophenyl)-3-pyridinylmethyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone    hydrochloride (1:1). This fraction was used directly in the next    reaction step.-   b) NH₃/iPrOH (20 ml) was added dropwise at 10° C. to a mixture of    6-[chloro(4-chlorophenyl)-3-pyridinylmethyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone    (0.0026 mol) in THF (15 ml). The mixture was brought to room    temperature, stirred for 2 hours, poured out into ice water and    extracted with EtOAc. The organic layer was separated, dried    (MgSO₄), filtered, and the solvent was evaporated. The residue    (1.5 g) was purified by column chromatography over silica gel    (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.2; 15–40 μm). The pure fractions    were collected and the solvent was evaporated, yielding 0.65 g (48%)    of    6-[amino(4-chlorophenyl)-3-pyridinylmethyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone,    melting point 90° C.

EXAMPLE B16

2,2,2-trichloroethyl carbonochloridic acid ester (0.00724 mol) was addedto a solution of6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone(R121550), obtained in Example B3 (0.00145 mol) in THF (10 ml). Themixture was stirred at 80° C. for 2 hours and poured out into ice water.AcOEt was added and the mixture was basified with potassium carbonate.The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue (1.6 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH/96/4/0.2;15–40 μm). The pure fractions were collected and the solvent wasevaporated, yielding 0.32 g of a residue which was further purified bycolumn chromatography over silica gel (eluent: toluene/2-propanol/90/10;kromasyl 5 μm). yielding 0.139 g (14%) of[(4-chlorophenyl)[4-[2-(3-chlorophenyl)ethyl]-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-carbamicacid, 2,2,2-trichloroethyl ester, MS (MH⁺) m/e: 691, 693, 695, 697, 699.

EXAMPLE B17

H₂SO₄ concentrated (3 drops) was added to a mixture ofα-(4-chlorophenyl)-5-[2-(3-chlorophenyl)ethyl]-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinoline-7-methanol,obtained in Example B6 (0.0013 mol) in 1,2-ethanediol (7 ml). Themixture was stirred at 125° C. for 18 hours, then poured out intoice/K₂CO₃ 10% and extracted with DCM. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated till dryness.The residue (0.88 g) was purified by column chromatography over silicagel (eluent: toluene/iPrOH/NH₄OH 85/15/1; 15–40 μm). The pure fractionswere collected and the solvent was evaporated. The residue (0.4 g, 54%)was crystallized from CH₃CN. The precipitate was filtered off and dried,yielding 0.32 g (43%) of2-[(4-chlorophenyl)[5-[2-(3-chlorophenyl)ethyl]tetrazolo[1,5-α]quinazolin-7-yl](1-methyl-1H-imidazol-5-yl)methoxy]-ethanol,melting point 229° C.

EXAMPLE B18

H₂SO₄ (3 drops) was added to a mixture ofα-(4-chlorophenyl)-5-[2-(3-chlorophenyl)ethyl]α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinoline-7-methanol,obtained in Example B6 (0.0013 mol) in 2-methoxy-ethanol (7 ml). Themixture was stirred at 125° C. for 48 hours, poured out into ice/K₂CO₃10% and extracted with DCM. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated till dryness. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 97.5/2.5/0.1; 15–40 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.12 g, 16%) wasdissolved in 2-propanone/DIPE and converted into the ethanedioic acidsalt. The precipitate was filtered off and dried, yielding 0.1 g (11%)of5-[2-(3-chlorophenyl)ethyl]-7-[(4-chlorophenyl)(2-methoxyethoxy)(1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-α]quinolineethanedioate (1:1) hydrate (1:1), melting point 156° C.

EXAMPLE B19

BuLi 1.6M in hexane (0.014 mol) was added dropwise at −70° C. to amixture of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0074 mol)in THF (40 ml) under N₂ flow. The mixture was stirred at −70° C. for 30minutes, then brought to 0° C., stirred for 30 minutes and cooled againto −70° C. Intermediate 16 (0.0038 mol) was added portionwise. Themixture was stirred for 30 minutes, then brought to 0° C., stirred atroom temperature for a week-end, poured out into water and extractedwith EtOAc. The organic layer was separated, dried (MgSO₄), filtered,and the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.2;15–40 μm). The pure fractions were collected and the solvent wasevaporated, yielding 0.22 g (10%) of4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone,MS (MH⁺) m/e: 551, 553, 555.

EXAMPLE B20

Sodium nitrite (0.0007 mol) was added at 0° C. to a mixture of nitricacid (0.0007 mol) in water (1 ml). A solution of4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone,obtained in Example B19 (0.0007 mol) in THF (3 ml) was added dropwise(very exothermic reaction). The mixture was stirred at room temperaturefor 30 minutes, poured out into ice water and extracted with DCM. Theorganic layer was separated, washed with K₂CO₃ 10%, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over kromasyl (eluent: CH₂Cl₂/CH₃OH/NH₄OH96/4/0.4; 5 μm). The pure fractions were collected and the solvent wasevaporated. The residue (0.25 g) was crystallized from CH₃CN. Theprecipitate was filtered off and dried, yielding 0.12 g (32%) of4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone,melting point 200° C.

The following compounds were prepared analogous to the one of the aboveexamples (the example number analogous to which they were prepared isindicated between square brackets after the compound number).

[B1], mp. 185.2° C.

[B1], mp. 215.5° C.

[B1], mp. 162.4° C.

[B1], mp. 223.8° C.

[B1], mp. 173.2° C.

[B8], mp. 260° C.  

[B8], mp. 186° C.  

[B8], mp. 175° C.  

[B9], mp. 230° C.  

[B8], mp. 230° C.  C. Pharmacological Example.

EXAMPLE C1 “In Vitro Assay for Inhibition of Farnesyl ProteinTransferase”

An in vitro assay for inhibition of farnesyl transferase was performedessentially as described in WO 98/40383, pages 33–34.

EXAMPLE C2 “Ras-Transformed Cell Phenotype Reversion Assay”

The ras-transformed cell phenotype reversion assay was performedessentially as described in WO 98/40383, pages 34–36.

EXAMPLE C3 “Farnesyl Protein Transferase Inhibitor Secondary TumorModel”

The farnesyl protein transferase inhibitor secondary tumor model wasused as described in WO 98/40383, page 37.

D. Composition Example: Film-coated Tablets

Preparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml ofwater. The wet powder mixture is sieved, dried and sieved again. Thenthere are added 100 g microcrystalline cellulose and 15 g hydrogenatedvegetable oil. The whole is mixed well and compressed into tablets,giving 10.000 tablets, each comprising 10 mg of a compound of formula(I).

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

1. A compound of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemicallyisomeric form thereof, wherein: r and s are each independently 0, 1, 2,3, 4 or 5; t is 0, 1, 2 or 3; >Y¹—Y²— is a trivalent radical of formula>C═N—  (y-1)>C═CR⁹—  (y-2)>CH—NR⁹—  (y-3)>CH—CHR⁹—  (y-4) wherein R⁹ is hydrogen, halo, cyano, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, halocarbonyl, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, aryl or a group of formula —C₁₋₆alkyl-NR²²R²³,—C₂₋₆alkenyl-NR²²R²³, —CONR²²R²³ or —NR²²—C₁₋₆alkyl-NR²²R²³; Z is —O—,—S—, —SO—, —SO₂—, —NR²²—, -Alk-, C₂₋₄alkenediyl, —O-Alk-, -Alk-O—,—S(O)₀₋₂-Alk-, -Alk-S(O)₀₋₂, —OC(O)-Alk-, -Alk —OC(O)—, —NR²²-Alk-,-Alk-NR²²—, —NR²²— C(O)— or —C(O) —NR²²— (wherein Alk is C₁₋₆alkanediyl)and wherein the Alk or alkenediyl moiety may be optionally substitutedby one or more substituents independently selected from C₁₋₆alkyl,C₁₋₆alkyloxy, arylC₁₋₆alkyl or Ar², and where necessary to establish theconfiguration of any Z group, the first atom recited above in any suchgroup being that which is linked to the Y¹ grouping in formula (I); eachR¹ and R² is independently azido, hydroxy, halo, cyano, nitro,C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,hydroxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, R²⁴SC₁₋₆alkyl, trihalomethyl,arylC₁₋₆alkyl, Het²C₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³,—C₁₋₆alkylNR²²C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylNR²²-Het²,—C₁₋₆alkylNR²²—C₁₋₆alkyloxyC₁₋₆alkyl,—C₁₋₆akylNR²²—C₁₋₆alkyl-S—C₁₋₆alkyl-Ar²,—C₁₋₆alkylNR²²—C₁₋₆alkyl-S—C₁₋₆alkyl, —C₁₋₆alkylNR²²C₁₋₆alkyl-Ar²(wherein the C₁₋₆alkyl moiety adjacent to the Ar² is optionallysubstituted by C₁₋₆alkyloxycarbonyl), —C₁₋₆alkylNR²²C₁₋₆alkyl-Het²,—C₁₋₆alkylNR²²COC₁₋₆alkyl, —C₁₋₆alkylNR²²COAlkAr², —C₁₋₆alkylNR²²COAr²,C₁₋₆alkylsulphonylaminoC₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, —OC₁₋₆alkyl-NR²²R²³, trihalomethoxy,arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, C₁₋₆alkylthio, C₂₋₆alkenyl,cyanoC₂₋₆alkenyl, —C₂₋₆alkenyl-NR²²R²³, hydroxycarbonylC₂₋₆alkenyl,C₁₋₆alkyloxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl,hydroxyC₁₋₆alkylcarbonyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,—CONR²²R²³, —CONR²²—C₁₋₆alkyl-NR²²R²³, —CONR²²—C₁₋₆alkyl-Het²,—CONR²²—C₁₋₆alkyl-Ar², —CONR²²-Het², —CONR²²Ar², —CONR²²—O—C₁₋₆alkyl,—CONR²²—C₁₋₆alkenyl, —NR²²R²³, —OC(O)R²⁴, —CR²⁴═NR²⁵, —CR²⁴═N—OR²⁵,—NR²⁴C(O) NR²²R²³, —NR²⁴SO₂R²⁵, —NR²⁴C(O)R²⁵, —S(O)₀₋₂R²⁴, —SO₂NR²⁴R²⁵,—C(NR²⁶R²⁷)═NR²⁸ —Sn(R²⁴)₃, —SiR²⁴R²⁴R²⁵, —B(OR²⁴)₂, —P(O)OR²⁴OR²⁵,Ar²oxy, Het²-oxy, or a group of formula -Z, —CO-Z or —CO—NR^(y)-Z inwhich R^(y) is hydrogen or C₁₋₄alkyl and Z is phenyl or a 5- or6-membered heterocyclic ring containing one or more heteroatoms selectedfrom oxygen, sulphur and nitrogen, the phenyl or heterocyclic ring beingoptionally substituted by one or two substituents each independentlyselected from halo, cyano, —COOR²⁴, aminocarbonyl, C₁₋₆alkylthio,hydroxy, —NR²²R²³, C₁₋₆alkylsulphonylamino, C₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkyloxy or phenyl; or two R¹ or R² substituents adjacent to oneanother on the phenyl ring may form together a bivalent radical offormula—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2)—O—CH═CH—  (a-3)—O—CH₂—CH₂—  (a-4)—O—CH₂—CH₂—CH₂—  (a-5)—CH═CH—CH═CH—  (a-6) p is0 to 5; R²⁰ and R²¹ are independently hydrogenor C₁₋₆ alkyl and are independently defined for each iteration of p inexcess of 1; R²² and R²³ are independently hydrogen, C₁₋₆ alkyl or—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or together with the adjacent nitrogenatom form a 5- or 6-membered heterocyclic ring optionally containingone, two or three further heteroatoms selected from oxygen, nitrogen orsulphur and optionally substituted by one or two substituents eachindependently selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, aminocarbonyl, mono- ordi-(C₁₋₆alkyl)aminocarbonyl, amino, mono- or di-(C₁₋₆alkyl)amino,C₁₋₆alkylsulfonylamino, oxime, or phenyl; R²⁴ and R²⁵ are independentlyhydrogen, C₁₋₆ alkyl, —(CR₂₀R₂₁)_(p)—C₃₋₁₀cycloalkyl or arylC₁₋₆alkyl;R²⁶, R²⁷ and R²⁸ are independently hydrogen and C₁₋₆alkyl or—C(O)C₁₋₆alkyl; R³ is hydrogen, halo, cyano, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,—C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkyl-CONR²²R²³, arylC₁₋₆alkyl, Het²C₁₋₆alkyl,C₂₋₆alkenyl, —C₂₋₆alkenyl NR²²R²³, C₂₋₆alkynyl, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, aryl, or Het²; or a radical of formula—O—R¹⁰  (b-1)—S—R¹⁰  (b-2)—NR¹¹R¹²  (b-3)—N═CR¹⁰R¹¹  (b-4) wherein R¹⁰ is hydrogen, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkylcarbonyl, aryl, a group of formula —NR²²R²³ or—C₁₋₆alkylC(O)OC₁₋₆alkyl NR²²R²³, or a radical of formula -Alk-OR¹³ or-Alk-NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl orarylC₁₋₆alkyl; R¹² is hydrogen, hydroxy, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,arylC₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆alkyloxy, a group offormula —NR²²R²³, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl,haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, Het²C₁₋₆alkylcarbonyl,arylcarbonyl, C₁₋₆alkyloxycarbonyl, trihaloC₁₋₆alkyloxycarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, aminocarbonyl, mono- ordi-(C₁₋₆alkyl)aminocarbonyl (wherein the alkyl moiety may optionally besubstituted by one or more substituents independently selected from aryland C₁₋₆alkyloxycarbonyl substituents) aminocarbonylcarbonyl, mono- ordi-(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula -Alk-OR¹³or -Alk-NR¹⁴R¹⁵; R¹³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)—C₃₋₁₀cycloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, aryl orarylC₁₋₆alkyl; R¹⁴ is hydrogen, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl orarylC₁₋₆alkyl; R¹⁵ is hydrogen, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl ,C₁₋₆alkylcarbonyl, aryl or arylC₁₋₆alkyl; R⁴ is a radical of formula

wherein R¹⁶ is hydrogen, halo, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylS(O)₀₋₂C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, a group offormula —NR²²R²³, —NHCOC₁₋₆alkyl, hydroxycarbonyl, C₁₋₆alkyloxycarbonylor aryl, R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aryl C₁₋₆alkyl,trifluoromethyl, trifluoromethylC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, mono- or di-(C₁₋₆alkyl)aminosulphonyl or—C₁₋₆alkyl P(O)OR²⁴OR²⁵; R¹⁸ is hydrogen, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, arylC₁₋₆alkyl or C₁₋₆alkyloxyC₁₋₆alkyl;R^(18a) is hydrogen, —SH or —SC₁₋₄alkyl; R⁵ is cyano, hydroxy, halo,C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, or a group of formula —NR²²R²³ or —CONR²²R²³; R⁶is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl,—C₁₋₆alkylCO₂R²⁴, aminocarbonylC₁₋₆alkyl, —C₁₋₆alkyl-NR²²R²³, R²⁴SO₂,R²⁴SO₂C₁₋₆alkyl, —C₁₋₆alkyl-OR²⁴, —C₁₋₆alkyl-SR²⁴,—C₁₋₆alkylCONR²²—C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylCONR²²—C₁₋₆alkyl-Het²,—C₁₋₆alkyl CONR²²—C₁₋₆alkyl-Ar², —C₁₋₆alkyl CONR²²-Het², —C₁₋₆alkylCONR²²Ar², —C₁₋₆alkyl CONR²²—O—C₁₋₆alkyl, —C₁₋₆alkyl CONR²²—C₁₋₆alkenyl,-Alk-Ar² or -Alk-Het²; R⁷ is oxygen or sulphur; or R⁶ and R⁷ togetherform a trivalent radical of formula: —CR³⁰═CR³¹—N═ (x-1),—CR³⁰═CR³¹—CR³²═ (x-6), —CR³⁰═N—N═ (x-2), —CR³⁰═N—CR³¹═ (x-7),—C(═O)—NH—N═ (x-3), —C(═O)—NH—CR³⁰═ (x-8), —N═N—N═ (x-4), —N═N—CR³⁰═(x-9), or —N═CR³⁰—N═ (x-5), —CH₂—(CH₂)_(0–1)—CH₂—N═ (x-10),

wherein each R³⁰, R³¹ and R³² are independently hydrogen, C₁₋₆ alkyl,—OR²⁴, —COOR²⁴, —NR²²R²³, —C₁₋₆ alkylOR²⁴, —C₁₋₆ alkylSR²⁴,R²³R²²NC₁₋₆alkyl-, —CONR²²R²³, C₂₋₆alkenyl, C₂₋₆alkenylAr²,C₂₋₆alkenylHet², cyano, amino, thio, C₁₋₆ alkylthio, —O-Ar², —S—Ar² orAr²; Ar² is phenyl, naphthyl or phenyl or naphthyl substituted by one tofive substituents each independently selected from halo, hydroxy, cyano,nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryloxy, —NR²²R²³,C₁₋₆alkylsulfonylamino, oxime or phenyl, or a bivalent substituent offormula —O—CH₂—O— or —O—CH₂—CH₂—O—; Het² is a mono- or bi-cyclicheterocyclic ring containing one or more heteroatoms selected fromoxygen, sulphur and nitrogen, and optionally substituted by one or twosubstituents each independently selected from halo, hydroxy, cyano,nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³,C₁₋₆alkylsulfonylamino, oxime or phenyl.
 2. A compound according toclaim 1 in which: r and s are each independently 0, 1 or 2; t is 0 or 1;>Y¹—Y²— is a trivalent radical of formula>C═N—  (y-1)>C═CR⁹—  (y-2) wherein R⁹ is hydrogen, cyano, halo, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, hydroxycarbonyl or aminocarbonyl; Z is C₁₋₂alkanediyl; R¹ is halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, hydroxycarbonylC₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy,C₁₋₆alkylthio, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³ or—CH═NOR²⁵; or two R¹ substituents adjacent to one another on the phenylring may independently form together a bivalent radical of formula—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2) R² is halo, cyano, nitro, C₁₋₆alkyl,cyanoC₁₋₆alkyl, —C₁₋₆alkyl NR²²R²³; cyanoC₂₋₆alkenyl, —NR²²R²³, —CHO,—CR²⁴═N—OR²⁵, C₁₋₆alkyloxycarbonyl or —CONR²²R²³; or two R² substituentsadjacent to one another on the phenyl ring may independently formtogether a bivalent radical of formula—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2) R³ is hydrogen, C₁₋₆alkyl,—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, —C₁₋₆alkyl NR²²R²³,Het²C₁₋₆alkyl, —C₂₋₆alkenylNR²²R²³, or -Het², or a group of formula—O—R¹⁰  (b-1)—NR¹¹R¹²   (b-3), wherein R¹⁰ is hydrogen, C₁₋₆alkyl, or—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or a group of formula -Alk-OR¹³ or-Alk-NR¹⁴R¹⁵; R¹¹ is hydrogen or C₁₋₆alkyl; R¹² is hydrogen, hydroxy,C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl, Het²C₆alkylcarbonyl,aminocarbonyl, or a radical of formula -Alk-OR¹³ or Alk-NR¹⁴R¹⁵; whereinAlk is C₁₋₆alkanediyl; R¹³ is hydrogen, C₁₋₆alkyl or—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl; R¹⁴ is hydrogen, C₁₋₆alkyl, or—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl; R¹⁵ is hydrogen or C₁₋₆alkyl; R⁴ is aradical of formula (c-2) or (c-3) wherein R¹⁶ is hydrogen, halo orC₁₋₆alkyl, R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,C₁₋₆alkyloxyC₁₋₆alkyl or trifluoromethyl; R¹⁸ is hydrogen, C₁₋₆alkyl or—(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl; and R^(18a) is hydrogen; R⁵ is cyano,halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyloxy or C₁₋₆alkyloxycarbonyl; R⁶is hydrogen, C₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, —C₁₋₆alkylC(O)NR²² R²³,-Alk-Ar², -AlkHet² or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl; R⁷ is oxygen orsulphur; or R⁶ and R⁷ together form a trivalent radical of formula(x-1), (x-2), (x-3), (x-4) or (x-9); and Het² is a 5- or 6-memberedmonocyclic heterocyclic ring containing one, two or three heteroatomsselected from oxygen, sulphur or nitrogen for example pyrrolidinyl,imidazolyl, triazolyl, pyridyl, pyrimidinyl, furyl, morpholinyl,piperazinyl, piperidinyl, thiophenyl, thiazolyl or oxazolyl, or a 9- or10-membered bicyclic heterocyclic ring especially one in which a benzenering is fused to a heterocyclic ring containing one, two or threeheteroatoms selected from oxygen, sulphur or nitrogen for exampleindolyl, quinolinyl, benzimidazolyl, benzotriazolyl, benzoxazolyl,benzothiazolyl or benzodioxolanyl.
 3. A compound according to claim 1 inwhich: r is 0, 1 or 2; s is 0 or 1; t is 0; >Y¹—Y²— is a trivalentradical of formula (y-1) or (y-2), wherein R⁹ is hydrogen or halo; Z isC₁₋₂ alkanediyl; R¹ is halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, or twoR¹ substituents ortho to one another on the phenyl ring mayindependently form together a bivalent radical of formula (a-1); R² ishalo, cyano, nitro, —CHO, —CR²⁴═N—OR²⁵ (wherein R²⁴ is hydrogen and R²⁵is hydrogen or C₁₋₆alkyl), or two R² substituents ortho to one anotheron the phenyl ring may independently form together a bivalent radical offormula (a-1); R³ is hydrogen or a group of formula (b-1) or (b-3)wherein R¹⁰ is hydrogen or a group of formula -Alk-OR¹³; R¹¹ ishydrogen; R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy orC₁₋₆alkyloxy; Alk is C₁₋₆alkanediyl and R¹³ is hydrogen; R⁴ is a groupof formula (c-2) or (c-3) wherein R¹⁶ is hydrogen, halo or C₁₋₆alkyl;R¹⁷ is hydrogen or C₁₋₆alkyl; R¹⁸ is hydrogen or C₁₋₆alkyl; and R^(18a)is hydrogen; R⁶ is hydrogen, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,—C₁₋₆alkylCO₂R²⁴, —C₁₋₆alkylC(O)NR²²R²³, -Alk-Ar² or -AlkHet² orC₁₋₆alkyl; R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form atrivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9); andaryl is phenyl.
 4. A compound according to claim 1 in which: r is 0 or1, s is 1, t is 0, >Y¹—Y² is a trivalent radical of formula (y-1) or(y-2), Z is C₁₋₂alkanediyl, R¹ is halo, C₁₋₆alkyl or forms a bivalentradical of formula (a-1), R² is halo or cyano, R³ is hydrogen or aradical of formula (b-1) or (b-3) (wherein R¹⁰ is hydrogen or -Alk-OR¹³,R¹¹ is hydrogen, R¹² is hydrogen or C₁₋₆alkylcarbonyl, and R¹³ ishydrogen); R⁴ is a radical of formula (c-2) or (c-3) (wherein R¹⁶ ishydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl and R^(18a) is hydrogen);R⁶ is hydrogen, C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴ (R²⁴═Hor Et), aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet²; and R⁷ is oxygenor sulphur; or R⁶ and R⁷ together form a trivalent radical of formula(x-2), (x-3) or (x-4).
 5. A compound according claim 1 in which: r is 0or 1, s is 1, t is 0, >Y¹—Y² is a trivalent radical of formula (y-1) or(y-2), Z is C₁₋₂ alkanediyl, R¹ is halo, R² is halo or cyano, R³ ishydrogen or a radical of formula (b-1) or (b-3) (wherein R⁹ is hydrogen,R¹⁰ is hydrogen, R¹¹ is hydrogen and R¹² is hydrogen orC₁₋₆alkylcarbonyl; R⁴ is a radical of formula (c-2) or (c-3) (whereinR¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl and R^(18a) ishydrogen); R⁶ is hydrogen, C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or—C₁₋₆alkylAr²; and R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form atrivalent radical of formula (x-2) or (x-4).
 6. A compound accordingclaim 1 in which: r and s are 1, t is 0, >Y¹—Y² is a trivalent radicalof formula (y-1) or (y-2), Z is —(CH₂)₂—, R¹ is 3-chloro, R² is 4-chloroor 4-cyano, R³ is a radical of formula (b-1) or (b-3) (wherein R⁹ ishydrogen, R¹⁰ and R¹¹ are hydrogen, and R¹² is hydrogen orC₁₋₆alkylcarbonyl); R⁴ is a radical of formula (c-2) or (c-3) (whereinR¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl, and R^(18a) ishydrogen); R⁶ is hydrogen, C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl or—C₁₋₆alkylAr²; and R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form atrivalent radical of formula (x-4).
 7. A compound selected from:6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-[2-(3-chlorophenyl)ethyl]-1-methyl-2(1H)-quinolinone;4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone;α-(4-chlorophenyl)-5-[2-(3-chlorophenyl)ethyl]-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-α]quinoline-7-methanamine;N-[(4-chlorophenyl)[5-[2-(3-chlorophenyl)ethyl]tetrazolo[1,5-α]quinolin-7-yl](1-methyl-1H-imidazol-5-yl)methyl]-acetamide;N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)[5-(2-phenylethyl)tetrazolo[1,5-α]quinolin-7-yl]methyl]-acetamide;and4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone;and their pharmaceutically acceptable salts.
 8. A process for thepreparation of a compound as claimed in claim 1 which comprises: a)cyclising a compound of formula (II):

with a reagent serving to form a compound of formula (I) in which R⁶ ishydrogen and R⁷ is oxygen; b) reacting a compound of formula (III):

in which W¹ represents a replaceable or reactive group, with a reagentserving either to react with or replace the W¹ group in compound (III)to form a compound of formula (I) in which R⁶ is hydrogen and R⁷ is anoxygen or sulphur group or to react with the W¹ group and the adjacentnitrogen atom to form directly or indirectly a compound of formula (I)in which R⁶ and R⁷ together form a trivalent radical selected fromformulae (x-1) to (x-10); or c) reacting a compound of formula (IV):

in which W² is a replaceable group, with an imidazole reagent serving toreplace the group W² with an R⁴ group of formula (c-1); or d) reacting acompound of formula (V):

with an imidazole reagent to form a compound of formula (I) in which R⁴is a group of formula (c-2), or with a3-mercapto-4-C₁₋₆alkyl-1,2,4-triazole reagent to form the corresponding3-mercapto-4-C₁₋₆alkyl-1,2,4-triazole derivative, which is optionallymethylated to form the corresponding 3-methylmercapto derivative, andsubsequently removing the 3-mercapto or 3-methylmercapto group to form acompound of formula (I) in which R⁴ is a group of formula (c-3) in whichR¹⁸ is a C₁₋₆alkyl group; or with a 3-bromopyridyl reagent to form acompound of formula (I) wherein R⁴ is a group of formula (c-4); or e)reacting a compound of formula (VI):

with a reagent serving to convert the said compound (VI) to a compoundof formula (I) in which R⁶ is hydrogen and R⁷ is oxygen; and optionallyeffecting one or more of the following conversions in any desired order:(i) converting a compound of formula (I) into a different compound offormula (I); (ii) converting a compound of formula (I) into apharmaceutically acceptable salt or N-oxide thereof; (iii) converting apharmaceutically acceptable salt or N-oxide of a compound of formula (I)into the parent compound of formula (I); and (iv) preparing astereochemical isomeric form of a compound of formula (I) or apharmaceutically acceptable salt or N-oxide thereof.
 9. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier, and anactive ingredient comprising a therapeutically effective amount of acompound of claim
 1. 10. A pharmaceutical composition comprising apharmaceutically acceptable carrier, and an active ingredient comprisinga therapeutically effective amount of a compound of claim
 2. 11. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier, and an active ingredient comprising a therapeutically effectiveamount of a compound of claim
 3. 12. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, and an activeingredient comprising a therapeutically effective amount of a compoundof claim
 4. 13. A pharmaceutical composition comprising apharmaceutically acceptable carrier, and an active ingredient comprisinga therapeutically effective amount of a compound of claim
 5. 14. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier, and an active ingredient comprising a therapeutically effectiveamount of a compound of claim
 6. 15. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, and an activeingredient comprising a therapeutically effective amount of a compoundof claim 7.